Oct. 15, 2020 10:45 UTC

KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded label for KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). The approval is based on results from the Phase 3 KEYNOTE-204 trial in which KEYTRUDA significantly reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.48-0.88; p<0.0027]) compared to brentuximab vedotin (BV). Additionally, median progression-free survival (PFS) was 13.2 months (95% CI, 10.9-19.4) for patients treated with KEYTRUDA and 8.3 months (95% CI, 5.7-8.8) for patients treated with BV. The FDA also approved an updated pediatric indication for KEYTRUDA for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after two or more lines of therapy.

An estimated 8,500 patients in the U.S., many of them 40 years of age or younger, will be diagnosed with cHL this year. Now patients with cHL who progress after frontline therapy have a new option in KEYTRUDA, which has demonstrated a clinically meaningful improvement in progression-free survival compared to brentuximab vedotin, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. At Merck, we are committed to improving outcomes for patients with cancer. Todays FDA approval builds upon our growing range of options for people with blood cancers.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

The patients with cHL who do not achieve remission following initial treatment or who relapse after transplantation face a poor prognosis, reflecting the unmet need for improved therapies in the relapsed/refractory setting, said Dr. John Kuruvilla, hematologist and associate professor of medicine, Princess Margaret Cancer Centre and University of Toronto. With this approval, KEYTRUDA has the potential to change the current standard of care and help these patients achieve better outcomes.

KEYTRUDA was previously approved under the FDAs accelerated approval process for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after three or more prior lines of therapy based on data from the KEYNOTE-087 trial. In accordance with accelerated approval regulations, continued approval was contingent upon verification and description of clinical benefit; these accelerated approval requirements have been fulfilled with the data from KEYNOTE-204.

This approval was reviewed under the FDAs Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. For this application, a modified Project Orbis was undertaken, and the FDA is collaborating with the Australian Therapeutic Goods Administration and Health Canada on their ongoing review of the application.

Data Supporting the Approval The approval was based on data from KEYNOTE-204 (NCT02684292), a randomized, open-label, active-controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized 1:1 to receive either KEYTRUDA 200 mg intravenously every three weeks or BV 1.8 mg/kg intravenously every three weeks.

Treatment was continued until unacceptable toxicity, documented disease progression or a maximum of 35 cycles (up to approximately two years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse less than 12 months after completion vs. relapse 12 months or more after completion). The main efficacy measure was PFS as assessed by blinded independent central review (BICR) using 2007 revised International Working Group (IWG) criteria.

Patients were enrolled and randomized to KEYTRUDA (n=151) or BV (n=153). The study population characteristics were median age of 35 years (range, 18 to 84); 57% male; 77% white, 9% Asian and 3.9% Black. The median number of prior therapies was two (range, 1 to 10) in the KEYTRUDA arm and three (range, 1 to 11) in the BV arm, with 18% in both arms having one prior line. Forty-two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy.

In KEYNOTE-204, KEYTRUDA reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.48-0.88; p=0.0027]) and showed a median PFS of 13.2 months (95% CI, 10.9-19.4). Median PFS was 8.3 months (95% CI, 5.7-8.8) for patients treated with BV. For PFS, in the KEYTRUDA arm, there were 81 patients (54%) with an event versus 88 patients (58%) in the BV arm. For patients treated with KEYTRUDA, the objective response rate (ORR) was 66% (95% CI, 57-73), with a complete response rate of 25% and a partial response rate of 41%. For patients treated with BV, the ORR was 54% (95% CI, 46-62), with a complete response rate of 24% and a partial response rate of 30%. The difference in ORRs is not statistically significant. Among the responding patients, median duration of response (DOR) was 20.7 months (range, 0.0+ to 33.2+) with KEYTRUDA and 13.8 months (range, 0.0+ to 33.9+) with BV.

In KEYNOTE-204, the median duration of exposure to KEYTRUDA was 10 months (range, 1 day to 2.2 years), with 68% receiving at least six months of treatment and 48% receiving at least one year of treatment. Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in those greater than or equal to 1% of patients included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from an unknown cause.

Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions that required dosage interruption in greater than or equal to 3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase and pneumonia. Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. The most common adverse reactions (greater than or equal to 20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash and cough (20% each).

About Hodgkin Lymphoma Hodgkin lymphoma is a type of lymphoma that develops in the white blood cells called lymphocytes, which are part of the immune system. Hodgkin lymphoma can start almost anywhere most often in lymph nodes in the upper part of the body, with the most common sites being in the chest, neck or under the arms. Worldwide, there were approximately 80,000 new cases of Hodgkin lymphoma, and more than 26,000 people died from the disease in 2018. In 2020, it is estimated nearly 8,500 people will be diagnosed with Hodgkin lymphoma in the United States. Classical Hodgkin lymphoma accounts for more than nine in 10 cases of Hodgkin lymphoma in developed countries.

About KEYTRUDA (pembrolizumab) Injection, 100 mg KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients. Pneumonitis occurred in 8% (31/389) of patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib) Immune-Mediated Hepatitis KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and post-marketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risk of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients; those 1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression. The most common adverse reactions (20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Lactation Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a 10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Mercks Focus on Cancer Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit http://www.merck.com/clinicaltrials.

About the Merck Access Program for KEYTRUDA At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting http://www.merckaccessprogram-keytruda.com.

About Mercks Patient Support Program for KEYTRUDA Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855-398-7832) or visit http://www.keytruda.com.

About Merck For more than 125 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the worlds most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit http://www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the company) includes forward-looking statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the companys management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the companys ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the companys patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the companys 2019 Annual Report on Form 10-K and the companys other filings with the Securities and Exchange Commission (SEC) available at the SECs Internet site (www.sec.gov).

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.

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Two teams of researchers have developed miniature models of the human heart that beat and function like the full-size organ. The team from Michigan State University (MSU) and Washington University in St. Louis developed a human heart organoid (hHO) that recapitulates embryonic heart development, providing an unmatched view into congenital heart defects. The organoid created by the researchers at the Medical University of South Carolina (MUSC) and Clemson University mimics the tissue dysfunction that occurs following a heart attack.

Organoids are self-assembling, 3D multicellular constructs that exhibit organ properties and structure to various degrees. Several processes have been developed to create them in recent years.

The MSU teams heart includes all the primary types of heart cells, as well as functional chambers and vascular tissues. These minihearts constitute incredibly powerful models in which to study all kinds of cardiac disorders with a degree of precision unseen before, said Aitor Aguirre, the studys senior author and assistant professor of biomedical engineering at MSUs Institute for Quantitative Health Science and Engineering.

Results of the groups work created quite a stir when it appeared on the preprint server bioRxiv and highlights were presented at the 2020 International Society for Stem Cell Research Annual Meeting. Weve received a lot of calls from researchers who want to use our process, Aguirre told BioWorld. The NIH and the American Heart Association provided funding for the study.

To create the approximately 1-mm diameter hHOs, the team combined several approaches developed over the last decade. They start with induced pluripotent cells ordinary cells from adults that are induced by the introduction of several genes to become pluripotent stem cells or master cells. The team then provides chemical signals that stimulate the cells to differentiate and mimic the process used in fetal development to create a heart.

In 15 to 20 days, the developmentally directed approach takes an undifferentiated ball of cells and gets to the point that the heart beats, has chambers, has cells organized in the way those cells are organized in the heart. At a molecular and cellular level, we are creating a heart, Aguirre noted.

The process is much simpler and easier to recreate than tissue engineering, as hundreds can be created simultaneously with minimal operator involvement and without the need for expensive machinery. Aguirre said the equipment required would be present already in any standard cell laboratory.

Currently, the team is using the miniaturized model heart to study developmental heart disorders. Thats crucial because, while congenital heart affects 1% of all newborns, there have been no good ways to study fetal heart development. You cant tell a pregnant woman, we want to take a biopsy, so its hard to study first-hand, Aguirre explained. With this process, the team can replicate much of fetal heart development without using fetal cells, bypassing all ethical concerns.

Since the publication of their initial results, Aguirre and his team have made further advances to more closely model the human heart. By further improving the development conditions, the researchers are now giving the organoids structural and locational cues needed to organize themselves better. Those new conditions have led to the formation of two chambers with heart looping, creating a shape that resembles a sausage more than a ball. In addition, they are growing hearts that are more sophisticated and demonstrate functioning of a somewhat older heart.

The researchers also are working on the development of vasculature that will enable the minihearts to grow larger and to create a multiorgan system in vitro that would be especially useful in studying pediatric cardiopulmonary development. Beyond gaining a better understanding of the basics of early heart development, the team hopes the model will provide greater insight into the impact of various chemicals and conditions, including environmental contaminants, maternal diabetes and medications.

The South Carolina process

Researchers at the MUSC and Clemson University took a somewhat different approach to creation of their human cardiac organoid. Like the MSU team, they began with induced pluripotent stem cells that divide and self-assemble. The spherical organoids are fabricated in vitro using four defined cell types that range in maturity from early stage to adult in ratios found in the heart. The process gives the microtissue a range of functionality but does not reproduce the developmental process of a heart.

The greater maturity of some of the tissue has an advantage for the teams research, however. The South Carolina contingent has focused on creating heart organoids that parallel the physiological conditions present during and immediately following a heart attack. Their work recently appeared in Nature Biomedical Engineering.

The model demonstrates the key features of pathological metabolic shifts, fibrosis and calcium handling. Furthermore, our transcriptomic analysis showed that there are comparable disease characteristics that are similar to that of the diseased adult heart, lead author Dylan Richards, a graduate of the MUSC Clemson bioengineering program and now a computational biologist at The Janssen Pharmaceutical Companies of Johnson & Johnson, told BioWorld.

To model the heart after a heart attack, we used low oxygen culture to create an oxygen-diffusion gradient in cardiac organoids combined with noradrenaline stimulation, Richards said. This method resulted in a structural and functional gradient, similar to that of a heart after a heart attack (dying tissue in the middle surrounded by dysfunctional regions surrounded by functional regions).

Using the model, the team found that the experimental drug JQ1 reduces the fibrotic and arrhythmic properties seen in diseased post-heart attack organoids. They also demonstrated that doxorubicin, commonly used in breast cancer treatment, had greater cardiotoxic impact in diseased hearts, in keeping with previous findings of greater risk associated with the chemotherapy in women with pre-existing cardiovascular disease.

The team is looking at drug-exacerbated cardiotoxicity and COVID-19-induced cardiac diseases. It will also be enhancing the model to include immune cells, to better understand the role the immune system plays in restructuring heart tissue after damage from oxygen-deprivation.

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Human heart organoids provide unmatched insight into cardiac disease and dysfunction - BioWorld Online

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Staff Writer| Lubbock Avalanche-Journal

By Elizabeth Herbert

A-J Media

A 16-year-old Lubbockite with rheumatoid arthritis recently banked her wisdom teeth for their high concentration of stem cells in the hope of using them in a future procedure.

Stem cells are undifferentiated cells, meaning they can become almost any specialized cell; researchers have been studying these cells to learn more about using them to treat ailments such as rheumatoid arthritis.

The oral and facial surgeon who removed the patients teeth, Dr. Robert Ioppolo, said there was virtually no downside to storing the teeth and cells because the procedure, which is necessary for most, is the same for the patient regardless.

Instead of putting (wisdom teeth) in a baggie, we put them in a vial; we put them in a little freezer-type cryopreservation box and off they go to the processing center, he said, so its very straightforward from our perspective, and it just provides an additional service to patients that we didnt have access to a few years ago.

Once the teeth have been sent to process at the Stemodontics lab, Ioppolo said specialists open the teeth and extrapolate the nerve tissue to obtain the stem cells.

The cool thing is that the stem cell population inside of wisdom teeth, especially in somebody thats young and healthy, is at its peak as far as the amount of cells, so the quantity, and also the quality of those cells, he said, so this is kind of a one-time opportunity that folks have to bank the best stem cells that they possibly can from their wisdom teeth.

Rheumatoid arthritis typically impacts adults. The Centers for Disease Control states 7.1% of people aged 18-44 years old report being diagnosed with arthritis; younger groups are not listed on the main, arthritis-related page.

Jamie Fields, the patients mother, said her daughter has undergone knee surgeries and is on medications but has not seen strong improvements in the seven months she has been receiving treatment.

Doctors tried a technique called microfracture in which tiny holes are drilled into the knee to produce new tissue, but this results in fibrocartilage and is more like scar tissue and less like the cushiony cartilage that joints need to function properly, according to an article from the Stanford Medicine News Center.

Preserving her daughters wisdom teeth and stem cells will cost Fields $2,000, but she said her alternative is to grow cells from the cartilage taken from a previous surgery which would cost about $46,000 for the graft alone and does not account for an accompanying procedure.

When I hear about these stem cells, Im like, Well, what if this would work, she said. If thats the route we have to take, then why not try this first?

Aside from surgeries, Fields said her daughters doctor prescribed medications to help slow or stop the dying cartilage behind her knee. There are many options, but medicines tend to have side effects and Fields said she does not want her daughter to have to use multiple, strong pharmaceuticals long-term.

He has a list, and he started her at the bottom of the list on the medications, and then he said we would just go up from there, but that way we dont do anything too harsh thats not needed, she said.

Rheumatoid arthritis tends to worsen with age, and Fields said her daughter, who already has a history of broken bones and surgeries, is impacted by her rheumatoid arthritis to the extent that she cannot participate in gymnastics, cheerleading or other fun activities she has enjoyed.

Fields could keep working down the line of medications most 16 year olds cannot pronounce, or she said she could save her daughters stem cells and wait for orthopedists to create a procedure that would use her daughters cells to help rejuvenate damaged areas.

This is a once-in-a-lifetime (opportunity), Fields said. If we dont do this now, where is she gonna get them from later, of her own?

Michael Longaker, Deane P. and Louise Mitchell Professor for the Department of Surgery and Co-Director for the Institute of Stem Cell Research and Regenerative Medicine at Stanford University, said using stem cells could help a number of issues due to the cells ability to change.

While we do some things really well, like cardiac bypass surgery or hip replacement et cetera, et cetera, itd be great if we could unlock the power of cells that can become other types of cells so that we could regenerate each of these things before they get to the point where they need a major operation, he said.

Stem cells can be found throughout the body, and removing wisdom teeth is a fairly routine procedure; the WebMD website states over 10 million wisdom teeth are removed annually.

Many of these teeth are disposed of, but Longaker pointed out that stem cells in wisdom teeth are unique to the individual and are great sources of stem cells.

In the soft part, the pulp, of those teeth are stem cells that - God forbid - that healthy, young patient whos having them removed, God forbid anything happens to them and they need something or they have a family history of disease - theyre all set and ready to go, he said.

Longakers teams research began with mice and found skeletal stem cells can be manipulated to become cartilage.

They used two major molecules, bone morphogenetic protein 2 and vascular endothelial growth factor, to help the cells start bone formation after microfracture yet stop the process halfway to create cartilage. Longaker said the next step in the research is to focus on larger animals; then human clinical trials can begin.

Stem cells from wisdom teeth would work best for things in the mouth such as bone and cartilage, but Longaker said the cells can be backed up, de-differentiated and guided in a dish to the point where the cell can become almost anything; once the cell is fully differentiated, or has changed into a specific type of cell the specialist intended, it can be implanted.

You take the stem cells from teeth and back them up, so to speak, so they can become almost any type of cell, and then you would guide them down the exit ramp, so to speak, to where you want them to go, he said.

It may be years before orthopedists use stem cells to improve arthritic conditions, but Longaker, who banked his own sons wisdom teeth, said advances happen regularly and that one never knows when their stem cells will be useful.

As a stem cell biologist, having someone already store stem cells that I could guide to become something else, God forbid they need it, that really makes sense to me, he said. I dont see a reason not to do it if a parent or patient wants to do it.

Although banking her daughters wisdom teeth will not yield immediate results, Fields said she believes god guided her on this path and that she has more to gain than to lose.

Our faith is really strong, and I believe that God has led us on this path to hopefully find something that we can do to help her because weve been on this path for so long and with no answers, she said.

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Recovery from experimental heart attacks can be improved with an injection of a mixture of heart muscle cells, endothelial cells and smooth muscle cells, but results are limited by poor engraftment and retention, plus there are concerns about potential tumorigenesis and heart arrhythmia.

Recent animal research in pigs has shown that using the exosomes naturally produced from a mixture of heart muscle cells, endothelial cells, and smooth muscle cells derived from human induced pluripotent stem cells yielded regenerative benefits that were the equivalent to the injected hiPSC-CCs.

Exosomes are membrane-bound extracellular vesicles that contain biologically active proteins, RNAs and microRNAs that are well known to participate in cell to cell communication, and are actively studied as potential clinical therapies for a wide range of conditions.

The hiPSC-CC exosomes are acellular and, consequently, may enable physicians to exploit the cardioprotective and reparative properties of hiPSC-derived cells while avoiding the complexities associated with tumorigenic risks, cell storage, transportation and immune rejection, said Ling Gao, Ph.D., and Jianyi Jay Zhang, M.D., Ph.D., University of Alabama at Birmingham corresponding authors of the study, published in Science Translational Medicine. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.

Studies involving large animals are required to identify, characterize and quantify all responses to potential treatments, prior to this study the feasibility of hiPSC-CC exosomes for cariad therapy had only been shown to be effective in mouse models and in vitro work.

The UAB studies involving juvenile pigs with experimental heart attacks had 1 of 3 treatments injected into the damaged myocardium: a mixture of cardiomyocytes, endothelial cells, and smooth muscle cells derived from human induced pluripotent stems cells, exosomes extracted from three cell types, and homogenized fragments from the cell types.

There were 2 primary findings from this study. Measurements of left ventricle function, infarct size, wall stress, cardiac hypertrophy apoptosis and angiogenesis in the animals treated with hiPSC-CCS, hiPSC-cc fragments or hiPSC-cc exosomes were found to be similar and significantly improved compared to those that recovered without any of the 3 treatments. Additionally, exosome therapy was found not to increase the frequency of arrhythmia.

During experiments with cells or aortic rings that were grown in culture, exosomes produced by hiPSC-CCs were found to promote blood vessel growth in cultured endothelial cells and isolated aortic rings. The exosomes also protected the cultured hiPSC-cardiomyocytes from the cytotoxic effect of serum-free lox oxygen media by reducing the programmed apoptosis cell death and by maintaining intracellular calcium homeostasis which had a direct beneficial effect on heart conductivity. Additionally, the exosomes also increased cellular ATP content which is beneficial as deficiencies in cellular ATP metabolism are believed to contribute to the progressive decline in heart function in those with left ventricle hypertrophy and heart failure.

Some of the in vitro beneficial effects were found to also be mediated by synthetic mimics of the 15 most abundant microRNAs that were found in the hiPSC-cc exosomes. It was noted that knowledge of the potential role of microRNAs in clinical application requires more research as it is far from complete.

The study: Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine, co-authors with Gao and Zhang are Lu Wang, Yuhua Wei, Prasanna Krishnamurthy, Gregory P. Walcott and Philippe Menasch, UAB Department of Biomedical Engineering. Menasch also has an appointment at the Universit de Paris, France. Gao is now at Tongji University School of Medicine, Shanghai, China.

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This is an overview of some of the biggest cardiology technology advances. These innovations are covered in more detail in the two-volume set titled "Emerging Technologies in Heart Diseases." These innovative technologies mark the midway of a technological revolution in patient care. Here are a list of 10 noteworthy new cardiac technologies:

The emergence of a ventricular assist device (VAD) has revolutionized the care of patients with advanced heart failure. Primarily developed as a bridge to transplantation, the VAD has been shown to prolong life and to improve the quality of life when a donor heart is not found. Older versions required the implantation of a bulky pump and required patients to ambulate with heavy, large external batteries and control units. Yet, several revolutionary improvements in device size, battery reliability, and even wireless charging technologies might make these devices physically unnoticeable in the coming years, and possibly decrease patient susceptibility to infections. In addition, various mechanical modifications and newer modes of operation have limited the rates of hemolysis, thrombosis, and secondary aortic valve insufficiency.

Miniature VAD. Source: Watt et al. Artificial Mechanical Hearts and Ventricular Assist Devices. In: Emerging Technologies for Heart Diseases, Vol. 1 - Treatments for Heart Failure and Valvular Disorders. 2020; Elsevier, Academic Press (AP). Pages 25-40.

Atrial fibrillation (AF or AFib) remains a leading cause of stroke, which in turn may be associated with devastating health consequences and mortality. Yet, oral anticoagulants and left atrial appendage (LAA) occlusion devices may not be appropriate for all patients or may be associated with life-threatening complications. In recent years, novel, device-based technologies for stoke prevention have evolved. Some focused on carotid implants, while newer devices have been designed for continuous embolic filtration at the level of the common aortic pathway. These approaches, which are currently being tested in preclinical studies, might be translated in the near future to treatments available for patients with increased bleeding risks.

Lariat LAA closure device device (SentreHeart Inc, Redwood, Calif.). Source: Goel et al. Percutaneous closure of the left atrial appendage for stroke prevention. In: Emerging Technologies for Heart Diseases, Vol. 2 - Treatments for Myocardial Ischemia and Arrhythmias. 2020; Elsevier, Academic Press (AP). Pages 961-977.

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Conformal electronics are flexible, stretchy, electronic devices that can diagnose and treat tissue malfunctions. They have high spatiotemporal resolution and are comprised of a system of various sensors and transducers. Conformal electronics assess multiple parameters to monitor and regulate cardiac tissue functions by following the shape of the epicardium or endocardium. The technology of conformal electronics can transform the current model of cardiac diagnostics and therapeutics by enabling the development of new equipment. Also, new minimally invasive methods to access the epicardial tissue are likely to facilitate clinical adoption of this technology.

Flexible electronics attached to the heart for cardiac monitoringSource: Yin et al. Organ Conformal Electronics for Cardiac Therapeutics. In: Emerging Technologies for Heart Diseases, Vol. 2 - Treatments for Myocardial Ischemia and Arrhythmias. 2020; Elsevier, Academic Press (AP). Pages 911-937.

Transcatheter Mitral Valve Repair (TMVR) technologies are expanding rapidly. They have the potential to become alternatives to surgery for specific patients. TMVR devices can be differentiated according to the portion of the mitral valve they are intended to repair: the leaflet, the annulus, or the chordae, and to remodel the ventricles. To date, early results of novel TMVR technologies seem promising but the long-term sustainability and effectiveness have not been determined. Yet, given the advancements in transcatheter technologies, it is convincible that in the future, mitral regurgitation will be treated mainly using a minimally invasive approach.

Carillon Mitral Contour System from Cardiac Dimensions can can be implanted for to reshape the annulus using TMVR. Source: Colli et al. Transcatheter Mitral Valve Therapies for Degenerative and Functional Mitral Regurgitation. In: Emerging Technologies for Heart Diseases, Vol. 1 - Treatments for Heart Failure and Valvular Disorders. 2020; Elsevier, Academic Press (AP). Pages 417-461.

Tissue engineering techniques that use cells and regenerative medicine to treat heart disease, are promising new approaches in cardiovascular research. Scaffolds (i.e., biomaterials used as supports), cells and appropriate growth factors are needed to enable reconstruction of new tissue. Because the biomaterial is integral to the functional integrity and attachment of human cells, generating the ideal scaffold remains one of the most challenging aspect of tissue engineering. A decellularized heart composed of native extracellular matrix can provide a complex, unique, and natural scaffold that offers the physical and chemical signals required for cardiac function.

Isolated cadaveric heart prior to and following decellularization. Source: Taylor, et al. Decellularization of Whole Hearts for Cardiac Regeneration. In: Emerging Technologies for Heart Diseases, Vol. 1 - Treatments for Heart Failure and Valvular Disorders. 2020; Elsevier, Academic Press (AP). Pages 291-310.

Patients with hemodynamic compromise may not be optimally balanced with an intra-aortic balloon pump (IABP). Therefore, various devices have been developed to provide other advanced measures of circulatory support. Although most centers have limited experience with these devices, they may be lifesaving in specific patients. Also, extracorporeal oxygenation (ECMO) provides patients the opportunity to avoid mechanical ventilation. This will prevent possible decreases in blood pressure due to anesthesia and reduced venous return. Small, portable devices aimed at providing ventilatory and circulatory support are being developed for these critical cases.

The Maquet CardioHelp ECMO system is an example of a small, lightweight, portable ECMO.

The global burden of congenital or acquired heart valve defects is high. Bioprosthetic or mechanical replacement valves are often used, although they have limitations. This is especially true for pediatric patients who continue to grow. A potential solution is developing an in situ tissue engineering approach. A synthetic, bioresorbable scaffold might lead to individualized replacements for heart valves. These might be less prone to infections and more suitable for pediatric populations.

Bioresorbable synthetic scaffold generated using electrospinning techniques. Source: Klouda et al. Heart Valve Tissue Engineering: Current Preclinical and Clinical approaches. In: Emerging Technologies for Heart Diseases, Vol. 1 - Treatments for Heart Failure and Valvular Disorders. 2020; Elsevier, Academic Press (AP). Pages 383-398.

Cardiac arrhythmias are a leading cause of morbidity and mortality worldwide. Although rhythm disorders may be efficiently treated with implantable cardioverter defibrillators (ICDs), the ability to accurately determine which patients will benefit from these measures is currently limited. Also, in patients who do not have an intracardiac device, delivery of external defibrillatory shocks shortly after the onset of arrhythmia may be lifesaving. Therefore, many efforts are invested in increasing the ability to predict upcoming events and calling for medical assistance. Computational tools generally known as artificial intelligence (AI) may soon enhance our ability to predict the occurrence of life-threatening arrhythmias and thereby, provide earlier preventive and the therapeutic interventions. The increase in the use of wearable cardiac monitoring devices and the ability to provide advanced analysis of ECG and other electrophysiological data are expected to further revolutionize the field of machine learning-based diagnostics in cardiology.

The consumer-grade Fitbit Sense offers AI to automatically detect atrial fibrillation. Read more in the articleFitbit ECG App to Identify Atrial Fibrillation Receives Regulatory Clearance in U.S. and Europe.

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Catheter ablation is used to prevent ventricular arrhythmias by damaging or destroying the causative tissue. Due to difficulties targeting the appropriate tissue, advanced technologies are needed. Electrophysiologic mapping has advanced significantly along with the techniques and tools that can be used to effectively eliminate the arrhythmic substrate. Combining these tools in the electrophysiology (EP) lab with robotic navigation systems may lead to more precise ablation procedures for difficult cases, while reducing exposure to radiation.

Stereotaxis Genesis Robotic Magnetic Navigation System, the latest system from the vendor with its first two installs taking place in 2020. Source: AbdelWahab et al. Electrophysiologic Mapping and Cardiac Ablation therapy for Prevention of Ventricular Tachycardia. In: Emerging Technologies for Heart Diseases, Vol. 2 - Treatments for Myocardial Ischemia and Arrhythmias. 2020; Elsevier, Academic Press (AP). Pages 683-723.

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Cardiac devices may be associated with complications including repeated need for battery replacement, lead failure, infections, and limited applicability in young patients. Recent, major breakthroughs in induced pluripotent stem cells technologies and transdifferentiation approaches may revolutionize treatment of bradyarrhythmias and heart failure. Ventricular and pacemaker cells have been generated both in vitro and in vivo in preclinical models. Upscaling technology based on cell (and gene) grafts to the organ level, ensuring graft survival, and guaranteeing long-term safety are needed before these innovative methods can be used to replace electrical cardiac pacemakers and to treat patients with heart failure.

TBX18 over expression induces transdifferentiation of cardiac myocytes towards pacemaker-like cells. Source: Vgh et al. Molecular therapies for bradyarrhythmias. In: Emerging Technologies for Heart Diseases, Vol. 2 - Treatments for Myocardial Ischemia and Arrhythmias. Elsevier, Academic Press (AP). Pages 811-840.

About the author: Udi Nussinovitch M.D., Ph.D., is the editor of the two-volume set titled "Emerging Technologies in Heart Diseases Vol. 1" and "Emerging Technologies in Heart Diseases Vol. 2."The books cover all the major technologies in use or under development, for the treatment of cardiovascular disorders. The books present information systematically and are the only reference that attempts to address the technological aspects of cardiovascular treatments. They present a very interesting read for anyone involved in the biomedical field, cardiovascular researchers and cardiologists, who aspire to learn about currently available technologies as well those in the pipeline.

Nussinovitch graduated from the Sackler Faculty of Medicine, Tel Aviv University, and received training at the Sheba Medical Center, Rambam Healthcare Center and Meir Medical Center, while concurrently earning a Ph.D. in cardiac electrophysiology from the Technion Institute of Technology, Haifa, Israel. Dr. Nussinovitch has dedicated his research to investigating novel therapeutic approaches for cardiac disorders and modulating the cardiac electrophysiologic substrate for therapeutic purposes. He is the Director of the Applicative Cardiovascular Research Center (ACRC), affiliated with Tel Aviv University. Dr. Nussinovitch founded several biotech companies, including InVatin Technologies and InSpira Oxygenation Technologies. He performs his clinical work at Meir Medical Center, a medical facility and leading referral center in Israel.

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What is New in Cardiology? A Review of All Major Emerging Technologies for Heart Diseases - Diagnostic and Interventional Cardiology

Cardiac Stem Cells Comments Off on What is New in Cardiology? A Review of All Major Emerging Technologies for Heart Diseases – Diagnostic and Interventional Cardiology | October 14th, 2020

The only curative approach to treating myelofibrosis (MF) at this time is hematopoietic stem cell transplant, but the treatment landscape for this patient population continues to expand, particularly since the identification of the JAK-STAT pathway as a potential target in 2005. Although the introduction of novel agents like JAK inhibitors have been promising for the treatment of patients with MF, there are more agents coming down the pipeline as well that will impact the way physicians treat this population.1

During the National Comprehensive Cancer Network (NCCN) 2020 Virtual Congress: Hematologic Malignancies, Aaron Gerds, MD, MS, assistant professor of medicine (hematology and medical oncology), Cleveland Clinic Taussig Cancer Institute, reviewed the current treatment landscape for patients with MF and whats to come for the treatment of this patient population as clinical trials continue to advance the field.

Treatments of MF focus on the symptoms of the disease. This is a very symptom-forward disease, Gerds explained during his presentation, pointing toward the 4 biggest challenges in treating MF.

Overall, 80% of patients have splenomegaly, 70% experience MF-associated symptoms, 60% to 85% have anemia or cytopenia, and the life expectancy is shortened, with the average time from diagnosis to death being 5 to 6 years in all comers.

Currently, the treatment landscape includes hydroxyurea to control counts, while the JAK inhibitors like ruxolitinib (Jakafi) and fedratinib (Inrebic) are known to control the symptoms and splenomegaly. Patients with lower grades of fibrosis can be treated with interferons as well.

For patients who are anemic, some of the available treatment options include lenalidomide (Revlimid), thalidomide (Thalomid), and danazol, and patients who are moving from MF into an acute leukemia can be treated currently with chemotherapy agents such as azacitidine and decitabine.

A promising advancement in the treatment landscape of MF includes the identification of the JAK-STAT pathway, which is targeted with JAK inhibitors. The first JAK inhibitor to receive approval from the FDA was ruxolitinib, followed by fedratinib. Additional agents from this class of drugs are in development as well, which are showing different clinical benefits than what have been observed with these initial agents.

Targeting the JAK-STAT has really been the centerpiece for the treatment of MF," said Gerds, "and you can see JAK inhibitors are all over the place, from low risk to high risk, from the top to the bottom, it's everywhere. It has really become a cornerstone treatment for MF.

Ruxolitinib received its approval in 2011 on the basis of the COMFORT-1 and COMFORT-2 studies, in which ruxolitinib was compared with placebo or best available therapy (BAT), respectively, in intermediate-2 and high-risk patients with MF. Overall, the agent was able to induce spleen volume reduction of 35% in 41.9% of patients by week 24 compared with 0.7% with placebo (P <.0001), while spleen volume was reduced in 28.5% by week 48 in the COMFORT-2 study versus 0% with BAT (P <.0001).2,3

Although ruxolitinib does not kill MF cells, a survival benefit has also been associated with ruxolitinib. According to a pooled analysis from both the COMFORT-1 and COMFORT-2 studies, the median overall survival (OS) in the ruxolitinib arms was 5.3 years (95% CI, 4.7-not evaluable [NE]) compared with 3.8 years (95% CI, 3.2-4.6) in the control arm (HR, 0.70; 95% CI, 0.54-0.91; P = .0065).

Fedratinib received approval in 2019 based on findings from the open-label phase 2 JAKARTA-2 and the randomized placebo-controlled phase 3 JAKARTA clinical trials. JAKARTA demonstrated that 47% of patients receiving 400 mg fedratinib and 49% receiving 500 mg had spleen volume reduction 35% at week 24, while in JAKARTA-2, this was achieved in 53% of patients with intermediate/high-risk MF who were resistant to prior ruxolitinib treatment and 63% of those who were intolerant to the therapy.4,5

Among other JAK inhibitors coming done the pipeline now for the treatment of MF, the 2 agents that are furthest along include pacritinib and momelotinib, which have also demonstrated interesting activity in clinical trials. However, no 2 JAK inhibitors are alike, Gerds explained during his presentation.

Ruxolitinib is a JAK1/2 inhibitor, while fedratinib targets JAK2 and also hits other targets, including FLT3, which may be the cause of some of the particular off-target effects observed with this agent, like diarrhea and nausea. Pacritinib is a JAK2 inhibitor that has very little sensitivity for JAK1, but it is known to have some off-target effects due to also hitting FLT3 and IRAK1, which may be important in this agent. Momelotinib, on the other hand, is a JAK1/2 inhibitor, but it also has off-target effects in ACVR1, which is suspected to help with anemia in some patients.

We can say that there's room for all these JAK inhibitors in the treatment of MF because they all are a little bit different, and they can be applied to different populations of patients with MF, Gerds explained. For example, momelotinib has a positive effect on patients with anemia.

Momelotinib has been evaluated in 2 large randomized phase 3 studies, the SIMPLIFY 1 and SIMPLIFY 2 clinical trials, in which momelotinib was evaluated in patients who were nave to JAK inhibition (n = 432) and those who were previously treated with ruxolitinib (n = 156), respectively.

Spleen volume reductions of 35% at week 24 were observed in 26.5% receiving momelotinib versus 29% with ruxolitinib (P = .011) in the SIMPLIFY 1 study and in 7% who received momelotinib versus 6% with BAT (P= .90) in the SIMPLIFY 2 study. The total symptom score reduction at week 24 with momelotinib was 28.4% versus 42.2% with ruxolitinib (P = .98) in the SIMPLIFY 1 study and 26% with momelotinib versus 6% with BAT (P = .0006) in the SIMPLIFY 2 study.6,7

The JAK1/2 inhibitor momelotinib appears to have the potential to improve anemia via suppression of hepcidin, Gerds said. Momelotinib has been shown to decrease production of hepcidin and to increase serum iron and erythropoiesis, which leads to transfusion independence and an increase in hemoglobin. This served as the rationale for a phase 2 study of 41 transfusion-dependent patients with MF, in which 41% of patients converted to transfusion independence and 78% of nontransfusion-independent patients achieved 50% decrease in transfusions with momelotinib.8

The phase 3 MOMENTUM (NCT04173494) study has been initiated to evaluate momelotinib at 200 mg daily plus placebo against danazol, which is a therapeutic approach for treating anemia, at 600 mg daily plus placebo. Patients enrolled in the study are randomized 2:1 to either the momelotinib or danazol arm. After spleen progression in the control arm, patients are able to cross over to receive momelotinib. This is a global study being conducted in North America, the European Union, and Asia Pacific. Patients must have received prior JAK inhibitor therapy and have symptomatic disease to be included in the study, as well as have anemia. This trial will be able to validate the value of momelotinib in treating anemic patients with MF.

Pacritinib has been evaluated in 3 key studies, including the phase 2 PAC203 study, and the phase 3 PERSIST-1 and PERSIST-2 studies. PAC203 was a dose-finding study in higher-risk patients with MF who previously received ruxolitinib, while PERSIST-1 included higher-risk JAK inhibitornave patients with any degree of anemia or thrombocytopenia and PERSIST-2 included patients with platelet counts 100,000/mcL, allowing for prior JAK inhibitor treatment as well.

Spleen volume reduction 35% at week 24 occurred in 19% of patients in the pacritinib arm versus 5% with BAT (P =.0003) in PERSIST-1, 18% in the pacritinib arm versus 3% with BAT (P =.001) in PERSIST-2. The spleen volume reduction 35% at week 24 in 18% of patients who received pacritinib in PAC203, and the total symptom scores reduced 50% in 7.4% of patients, which was also observed in PERSIST-2 in 25% of those receiving pacritinib and 14% BAT.9,10

Pacritinib was temporarily placed on a clinical hold due to an increased signal for potential cardiac and bleeding complications, but upon a second look at the data from the PERSIST studies, investigators determined that this was a very high-risk population that are very thrombocytopenic and prone to bleeding events.11

Without the JAK1 inhibition in pacritinib, thrombocytopenia is not as concerning as with other JAK inhibitors, Gerds said. The aim of the ongoing PACIFICA (NCT03165734) study is to potentially fulfill the unmet need for patients with MF who have platelet counts less than 50,000 and who are at risk for thrombocytopenic events.

PACIFICA, a randomized phase 3 study, is now ongoing to determine the efficacy of pacritinib compared with the physicians choice of therapy. The primary end point for the trial is spleen volume reduction at 24 weeks, and secondary end points include total symptom score at 24 weeks, OS, and patient global impression change at 24 weeks. Crossover is not allowed in this study.

In the COMFORT studies, the median time on ruxolitinib was around 3 years, but a real-world analysis demonstrated that the average may be much shorter, Gerds explained. Patients who discontinue treatment with ruxolitinib tend to do poorly, and the median OS is short. New treatments are needed to improve outcomes in this patient population.

Unlike in a disease like chronic myeloid leukemia, in which a single mutation could be targeted with a type of agent that would give significant long-term disease control, there are many other pathways outside of the JAK-STAT pathway that could also be targeted in MF, which is where research is now looking to. Momelotinib and pacritinib remain under evaluation in large randomized trials now, and these agents, as well as luspatercept for anemia, appear most promising in terms of becoming available for the treatment of patients with MF in the near future. However, other agents are coming down the pipeline as well that Gerds noted during his presentation.

Novel agent PRM-151 works well in reversing fibrosis in the bone marrow, and bromodomain and extraterminal (BET) inhibitors are also under evaluation in some ongoing studies that are heading into phase 3, such as CPI-0610 for the upfront and post-JAK inhibitor setting. BET inhibitors reduce inflammatory cytokine production in MF, and LSD1 inhibitors have been associated with epigenetic reprograming.

Another promising class of drugs coming down the pipeline for the treatment of MF include JAK2type 2 inhibitors, which hit a different target than the known JAK inhibitors. PI3K inhibitors appear to suppress neoplastic clonal hematopoiesis via cell arrest and apoptosis, while SMAC activation, MDM2, and Aurora kinase A can potentially increase apoptosis.

There is some rationale for targeting the mutant CALR trap, which remains on the horizon for the treatment of patients with MF, as well as chimeric antigen receptor (CAR) T-cell therapies and other novel therapeutic approaches.

Beyond that, we are only limited by our creativity and work that is being done by our colleagues in the lab, both basic science and translational labs, Gerds concluded. More therapeutic treatments will be needed in order to delay progression in early disease, and lead to cure without transplant.

References

1. Gerds A. Myeloproliferative neoplasms: emerging treatment options for myelofibrosis. Presented at: NCCN 2020 Virtual Congress: Hematologic Malignancies; October 9-10, 2020.

2. Verstovsek S, Mesa RA, Gotlib J, et al.A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

3. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

4. Pardanani A, Harrison C, Cortes JE, et al. Safety anf efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial.JAMA Oncol. 2015;1(5):643-51. doi:10.1001/jamaoncol.2015.1590

5. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.Lancet Haematol. 2017;4(7):e317-e324. doi:10.1016/S2352-3026(17)30088-1

6. Mesa RA, Kiladjian JJ, Catalano JV, et al. Mesa R, et al. SIMPLIFY-1: a phase iii randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-nave patients with myelofibrosis.J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418

7. Harrison C, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial.Lancet Haematol. 2018;5:e73-e81. doi:10.1016/S2352-3026(17)30237-5

8. Oh, ST Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial.Blood Adv. 2020 Sep 22;4(18):4282-4291. doi: 10.1182/bloodadvances.2020002662

9.Mesa RA et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.Lancet Haematol. 2017;4:e225-e236. doi: 10.1016/S2352-3026(17)30027-3

10. Mascarenhas J et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial.JAMA Oncol. 2018;4:652-659. doi: 10.1001/jamaoncol.2017.5818

11. CTI biopharma announces removal of full clinical hold on pacritinib. News Release. CTI BioPharma Corp. January 5, 2017. Accessed October 11, 2020. https://prn.to/2GT8PuD

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Treatment Options Expand Beyond JAK Inhibition for Patients With Myelofibrosis - Targeted Oncology

Cardiac Stem Cells Comments Off on Treatment Options Expand Beyond JAK Inhibition for Patients With Myelofibrosis – Targeted Oncology | October 14th, 2020

I am a clinical immunologist that happens to also be a stem cell scientist with 45 years of experience. The first CD34 bone marrow transplantation in 1978 was done at Roswell Park using FACS flow cytometry. We watch GvHD take hold to many leukemia patients to these brave patients trying to save their life with no way to treat them, until now with MSC (mesenchymal stem cells).

I watched many patients give their lives to science research for a chance of cures, which we had successes 40 years forward, if you get CML, CLL you have 98% of treatment or cure. CAR T and other treatments etc.

My concerns (are that) the media is presenting a perspective in vacuum of the stem cell world in California. Prop 71 put California in play and pushed embryonic research. The people of California need to protect their investment of $3.3 billion, or the industry leadership will be lost along with the clinical trials supported by CIRM. Please do not underestimate the RPE for blindness. #1 unmet medical need when the Japanese pharma Astellas bought Ocata in 2015 and put it on the shelf setting back embryonic research.

Lets look at say, Mesoblast, a Australian stem cell company and the leader in field with four studies. (They) had a setback recently of their BLA of SR aGvHD for kids under 12 years old (which is a death sentence) using MSC stem cells (approved for treatment in Japan for two years now) on the first stem cells for regenerative medicine to be approved the FDA, on Sept. 30, 2020. Mesoblast has 330 double blind studies for Covid19 treatment.

We will know before Christmas if FDA will approve these cells. MSC will be better than vaccinations, with super antigens stimulating the immune memory cells being develop by many companies and Federal government.

Two points: federal funding for embryonic research is not very well supported, and you cannot put a price tag on the patients who are willing to put their life on the line for hope and a chance.

Stay in the game California - do not be shortsighted.

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Yes on 14 | Mailbox | independentnews.com - Livermore Independent

Bone Marrow Stem Cells Comments Off on Yes on 14 | Mailbox | independentnews.com – Livermore Independent | October 14th, 2020

The globalRheumatoid Arthritis Stem Cell Therapymarket study presents an all in all compilation of the historical, current and future outlook of the market as well as the factors responsible for such a growth. With SWOT analysis, the business study highlights the strengths, weaknesses, opportunities and threats of each Rheumatoid Arthritis Stem Cell Therapy market player in a comprehensive way. Further, the Rheumatoid Arthritis Stem Cell Therapy market report emphasizes the adoption pattern of the Rheumatoid Arthritis Stem Cell Therapy across various industries.Request Sample Reporthttps://www.factmr.com/connectus/sample?flag=S&rep_id=1001The Rheumatoid Arthritis Stem Cell Therapy market report highlights the following players:The global market for rheumatoid arthritis stem cell therapy is highly fragmented. Examples of some of the key players operating in the global rheumatoid arthritis stem cell therapy market include Mesoblast Ltd., Roslin Cells, Regeneus Ltd, ReNeuron Group plc, International Stem Cell Corporation, TiGenix and others.

The Rheumatoid Arthritis Stem Cell Therapy market report examines the operating pattern of each player new product launches, partnerships, and acquisitions has been examined in detail.Important regions covered in the Rheumatoid Arthritis Stem Cell Therapy market report include:

North America (U.S., Canada)Latin America (Mexico, Brazil)Western Europe (Germany, Italy, U.K., Spain, France, Nordic countries, BENELUX)Eastern Europe (Russia, Poland, Rest Of Eastern Europe)Asia Pacific Excluding Japan (China, India, Australia & New Zealand)JapanMiddle East and Africa (GCC, S. Africa, Rest Of MEA)

The Rheumatoid Arthritis Stem Cell Therapy market report takes into consideration the following segments by treatment type:

Allogeneic Mesenchymal stem cellsBone marrow TransplantAdipose Tissue Stem Cells

The Rheumatoid Arthritis Stem Cell Therapy market report contain the following distribution channel:

HospitalsAmbulatory Surgical CentersSpecialty ClinicsHave Any Query? Ask our Industry Experts-https://www.factmr.com/connectus/sample?flag=AE&rep_id=1001

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The Rheumatoid Arthritis Stem Cell Therapy market report offers a plethora of insights which include:

Changing consumption pattern among individuals globally.Historical and future progress of the global Rheumatoid Arthritis Stem Cell Therapy market.Region-wise and country-wise segmentation of the Rheumatoid Arthritis Stem Cell Therapy market to understand the revenue, and growth lookout in these areas.Accurate Year-on-Year growth of the global Rheumatoid Arthritis Stem Cell Therapy market.Important trends, including proprietary technologies, ecological conservation, and globalization affecting the global Rheumatoid Arthritis Stem Cell Therapy market.

The Rheumatoid Arthritis Stem Cell Therapy market report answers important questions which include:

Which regulatory authorities have granted approval to the application of Rheumatoid Arthritis Stem Cell Therapy in Health industry?How will the global Rheumatoid Arthritis Stem Cell Therapy market grow over the forecast period?Which end use industry is set to become the leading consumer of Rheumatoid Arthritis Stem Cell Therapy by 2028?What manufacturing techniques are involved in the production of the Rheumatoid Arthritis Stem Cell Therapy?Which regions are the Rheumatoid Arthritis Stem Cell Therapy market players targeting to channelize their production portfolio?Get Full Access of the Report @https://www.factmr.com/report/1001/rheumatoid-arthritis-stem-cell-therapy-market

Pertinent aspects this study on the Rheumatoid Arthritis Stem Cell Therapy market tries to answer exhaustively are:

What is the forecast size (revenue/volumes) of the most lucrative regional market? What is the share of the dominant product/technology segment in the Rheumatoid Arthritis Stem Cell Therapy market? What regions are likely to witness sizable investments in research and development funding? What are Covid 19 implication on Rheumatoid Arthritis Stem Cell Therapy market and learn how businesses can respond, manage and mitigate the risks? Which countries will be the next destination for industry leaders in order to tap new revenue streams? Which new regulations might cause disruption in industry sentiments in near future? Which is the share of the dominant end user? Which region is expected to rise at the most dominant growth rate? Which technologies will have massive impact of new avenues in the Rheumatoid Arthritis Stem Cell Therapy market? Which key end-use industry trends are expected to shape the growth prospects of the Rheumatoid Arthritis Stem Cell Therapy market? What factors will promote new entrants in the Rheumatoid Arthritis Stem Cell Therapy market? What is the degree of fragmentation in the Rheumatoid Arthritis Stem Cell Therapy market, and will it increase in coming years?Why Choose Fact.MR?

Fact.MR follows a multi- disciplinary approach to extract information about various industries. Our analysts perform thorough primary and secondary research to gather data associated with the market. With modern industrial and digitalization tools, we provide avant-garde business ideas to our clients. We address clients living in across parts of the world with our 24/7 service availability.

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Covid-19 Lockdown Impact: Rheumatoid Arthritis Stem Cell Therapy Market Growth and Demand (YEAR), Projected Fact.MR - The Cloud Tribune

Bone Marrow Stem Cells Comments Off on Covid-19 Lockdown Impact: Rheumatoid Arthritis Stem Cell Therapy Market Growth and Demand (YEAR), Projected Fact.MR – The Cloud Tribune | October 14th, 2020

An appeal has gone out to help an 11-year-old girlwho needs a stem cell transplant from a stranger, to give her a second chance of life.

Arya was diagnosed with a rare blood disorder. But following a diagnosis of aplastic anaemia, a serious condition that occurs when the body stops producing enough new blood cells, she will also be starting immunosuppressant treatment.

This means her immune system isn't working as it should, putting her at a greater risk of infections.

To cure her aplastic anaemia Arya needs a lifesaving stem cell transplant. Blood cancer charity Antony Nolan is searching the worldwide stem cell registers for a donor whose tissue type matches Arya's and who is willing to donate their stem cells to help her live a normal life again.

However, the search for a perfect match is difficult for people like Arya, who is half Indian, with mixed ethnicity so she is sharing her story with Anthony Nolan in order to raise awareness of the need for more people of mixed race to join the stem cell register.

She said, "'They said it would be hard to find a donor for me because of my ethnicity but it isn't impossible. There is hope."

The best possible match for Arya is most likely to have the same background or mix of ethnicities. Currently, people with mixed Asian or other minority backgrounds have a 20% chance of finding a match from an unrelated donor, compared with nearly 70% for people with white, north European heritage.

Arya was diagnosed earlier this year and is receiving treatment at St Mary's Hospital, London.She added, 'When I first became unwell, I remember getting a stomach ache. At first it felt like a stitch but the pain didn't go away so I had more tests.'

These tests revealed something more serious. Arya's mum Brundha recalls: "Arya has always been fit and healthy, but life changed very quickly; all of a sudden we were talking to doctors about aplastic anaemia and Arya has had to stop many of the things she liked doing because her platelets, the tiny blood cells that help your body form clots, were low."

The family were given news of the treatment Arya would need to undergo and the need for a suitable donor.As the search continues, waiting for a match for Arya has inspired the Lloyd family to share their story. Their aim is to raise awareness of the need for more stem cell donors of mixed ethnicities to join the Anthony Nolan register and so increase the likelihood of finding a match for young people like Arya.

Brundha said: 'Because Arya is of mixed race, it was always unlikely we would find a match quickly. We have therefore started this appeal because we don't want to give up hope. It's a waiting game, but there could be someone out there who is a match. We also understand that younger people make better matches, so we would like to do all we can to make this more widely known.'

Aryas Consultant, Professor Josu de la Fuente, who is a Consultant Haematologist and Director of the Paediatric Bone Marrow Transplant Programme at Imperial College Healthcare in London said A well matched donor offers the best opportunity for Arya to establish normal blood production long-term and not to worry about the future.

"I will urge anyone, but particularly those of mixed ethnicity to consider joining the Anthony Nolan register so that no child with blood disorders faces an uncertain future: we can all contribute and be part of the solution.

Arya added: 'What stands out most for me are the bone marrow biopsies and being undergeneral anaesthetic for the first time.'

Rebecca Pritchard leads Anthony Nolan's work to recruit donors aged 1630 to its stem cell register. Rebecca says: 'Despite all she is going through, Arya is standing up to share her story in order to inspire people of mixed background to join the register. There is a potential lifesaver out there who could help her. If you're aged 1630 you can join the Anthony Nolan register online by completing a form and swabbing your cheeks with swabs we'll send in the post.

'Each time we're told a patient is in need of a transplant we'll check whether you're a match for them; if you're found to be a match you could give your stem cells to give hope to families like Arya's.'

Brundha said, 'We were unprepared for this and when it happens you want to know there is a source of donors for your child. That's why we're doing this to highlight the need. Being on the register could have a major impact on someone else's life. It's such an important thing you could do without realising.

"Families would be eternally grateful. You may never be called on, but if you are you could be a lifeline for someone. One person out there could be that person. It's a win-win for everybody.'

Arya added: 'The message I would like people to take away is Never give up hope and please join the register.

To find out more about joining the Anthony Nolan register, or to find out more about how you can support the charity click here

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'Never give up hope and please join the register' says 11-year-old in need of stem cell donor match - Asian Image

Bone Marrow Stem Cells Comments Off on ‘Never give up hope and please join the register’ says 11-year-old in need of stem cell donor match – Asian Image | October 14th, 2020

In the latest Stem Cell Banking market report, factors that are positively impacting the industry progression as well as the major threats & challenges existing in this domain are expounded. To unveil all the possible opportunities for business expansion, the study scrutinizes the regulatory and macroeconomic framework across the various geographies. It also delves into the competitive dynamics and evaluates how it will evolve during the forecast period. Further, it suggests strategies for dealing with the impact of the COVID-19.

Key highlights from COVID-19 impact analysis:

A gist of the regional landscape:

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Other highlights from the Stem Cell Banking market report:

Market Status:The complete details on Stem Cell Banking Market situation, principal regions, distribution channels, pricing structures are blanketed.

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Strategic Analysis Covered in TOC: - Key Topics Covered

Initially, the document offers an outline of the global market with a complete take a look at key drivers, constraints, challenges, traits and product types sold by using the employer. The file studies the Stem Cell Banking market capacity of key packages with the identity of forecast opportunities. The local evaluation with a focus on specific international locations and area of interest markets is presented. The pinnacle organization profiles with key-word market size and proportion estimation, revenue strategies, products, and other factors are studied.

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Stem Cell Banking Market to witness an impressive growth during the forecast period 2020 2025 - Express Journal

Bone Marrow Stem Cells Comments Off on Stem Cell Banking Market to witness an impressive growth during the forecast period 2020 2025 – Express Journal | October 14th, 2020

Photo composition: Claudia Garca Martnez

Dr. Odalis Mara de la Guardia Pea, an expert immunologist, describes as "encouraging" preliminary findings obtained at the conclusion of the first phase of clinical trials evaluating the use of stem cells in patients facing lung damage caused by COVID-19.

The study, begun during the month of May at the Cuban Institute of Hematology and Immunology (IHI), was undertaken with a view toward eliminating or reducing interstitial inflammatory or fibrotic lung lesions following the infection.

The doctor, also an infectious disease specialist and head of External Services at the IHI, explains that the research will have significant impact "if, as we hope, stem cell therapy produces positive results in these patients with pulmonary alterations post-COVID-19.

"If the treatment is effective, it will be generalized across the entire country, improving the quality of life and respiratory capacity of these patients," she stated with the enthusiasm of someone devoted to the most important mission in the world: saving lives.

THE LUNG, THE "TARGET" ORGAN

De la Guardia Pea commented that, although SARS-COV-2 has a variety of dissimilar effects (cardiovascular, renal, cerebral, vascular, in distal or lower limbs, and others); the "target" organ in the case of COVID-19 is the lung, in which patients experience the most serious impact, both during the disease and once they have recovered, a pattern being studied internationally.

"We have detected cases, specifically in Cuban patients, who have presented this kind of affectation, especially those who have suffered symptoms over a longer period. Among those visited for the study, there were cases of important pulmonary alterations, which is the most frequent, but perhaps not the most serious," the specialist continued.

RECRUITMENT OF VOLUNTEERS

"These recruitment consultations were atypical, as they were done in the field, visiting the homes of recovered patients," the doctor explained, adding that potential volunteers needed to meet several criteria for inclusion in the clinical trials.

Those selected were between 18 and 70 years of age, of both sexes, who had contracted COVID-19 thirty days prior to the trial treatment, testing negative on a PCR at the time of recruitment, and exhibited respiratory symptoms since the beginning of the disease.

Specifically sought for the trials were patients who experienced a more torpid evolution of the disease, those who were hospitalized for more than 20 days, requiring oxygen, assisted ventilation, or the use of some aerosol as treatment, upon reaching serious or critical condition.

"More than 130 homes were visited over almost three months, from May to June; and 141 patients were interviewed, of which about 50 were studied. Twenty patients were included in the trial, which was the determined number," the doctor reported.

PULMONARY SEQUELAE

"During the investigation, several long term effects of COVID-19 were noted, although the most frequent involved the lungs. In some cases, indications of pulmonary fibrosis were detected, a condition that cannot be completely corrected, and can only be treated to increase lung capacity and improve quality of life," the doctor explained.

"The study is still in progress. The first phase has been completed, but there is some time remaining before final evaluation of the patients. What we can say is that, thus far, we are very happy with the results we have observed, they are encouraging," she emphasized.

UNFORGETTABLE STORIES

-Could you recount some stories that particularly impacted you?

-The first day I went out to recruit volunteers, I arrived at the home of a patient who, when she opened the door, exhibited obvious difficulty breathing, evident in plain sight.

We conducted the interview and learned that she experienced this difficulty on a daily basis, five weeks after being diagnosed with COVID-19 and 15 days after a negative PCR test.

This case was significant because we became aware of the lingering effects some patients face, who after having the disease, being discharged and completing all treatment, can have symptoms for a long time.

On another occasion, a patient received us effusively, grateful that he would continue to be treated, that he would receive some follow-up. This attitude was very common in many cases, confirming for us that the patients we visited were still feeling unwell, despite having recovered and been discharged from the hospital.

YOU CAN BE ASYMPTOMATIC OR YOU CAN DIE

"You can be infected and be asymptomatic, or develop the most severe symptoms of the disease and die. This is random, no one understands or can control it," the specialist warns, emphasizing the importance of being fully conscious of taking care of ourselves, since anyone can develop an aggressive case of COVID-19.

"I agree with everything Professor Durn says every day at nine o'clock in the morning, about how measures must be maintained and complied with: the use of facemasks, hand washing, shoe disinfection (with doormats soaked in 0.5% hypochlorite at the entrance to common areas), social distancing, and collective discipline.

"The population must take care; success in containing the pandemic lies in individual responsibility," she concluded.

STEM CELL TREATMENT

-When the patient is included in the study, treatment begins by injecting the granulocyte colony stimulating factor, Ior Leukocim, a product manufactured at Cubas Center for Molecular Immunology, to achieve the mobilization of stem cells from the bone marrow to the bloodstream.

-Subsequently, the patient's blood is extracted and mononuclear cells are separated and concentrated.

-This pool of cells includes hematopoietic and non-hematopoietic stem cells, which have immune-regulatory properties and promote the disappearance of lesions and the reconstitution of lung tissue.

-The cells are infused intravenously.

-The patient is evaluated one month following treatment and again at six months, to determine the clinical efficacy of the stem cell therapy.

Source: Granma interview with Consuelo Macas Abraham, director of the National Institute of Hematology and Immunology.

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The global blood and bone marrow cancer treatment market was valued at $38.8B (approx 32.8B) in 2018 and is reportedly expected to reach $74.9B (approx 63.4B) by 2027, expanding at a CAGR of 7.7% from 2019 to 2027.

Blood cancer begins in the bone marrow which is the integral source of stem cells, which are later differentiated into different types of blood cells in the human body. Researchers have stated that approximately 1.85 million new cases of blood cancer will be diagnosed by 2040 throughout the globe.

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Europe holds a market share of 30.8% owing to the supportive regulatory framework provided by the European Medical Agency for the development and sale of medication for the treatment of blood cancer.

In the recent development, blood and bone marrow cancer treatment developer Priothera Limited, has raised 30M in its Series A round of funding led by Fountain Healthcare Partners with participation from co-lead investor HealthCap and funds managed by Tekla Capital Management, LLC, as well as EarlyBird Venture Capital.

According to the medtech startup, the raised funds will be used to progress the clinical development of mocravimod a modulator of sphingosine 1 phosphate (S1P) receptors, to enhance the curative potential of allogenic hematopoietic stem cell transplantation (HSCT) for treating AML.

Priothera expects to generate further randomised clinical data in high-risk AML patients with these funds.

Dublin-based Priothera was founded in 2020 by Drs. Florent Gros and Dhaval Patel. Joining the founding team include experienced industry executive, Dr. Christoph Bucher, Dr. Simone Seiter, and CFO Brice Suire.

The company claims to be leading the way in developing orally applied sphingosine 1 phosphate (S1P) receptor modulators for haematological malignancies. S1P receptor modulators have been suggested to largely reduce egress of T cell subsets from lymphatic tissues allowing for dual inhibition of graft-versus-host-disease (GvHD) and enhancing graft-versus-leukemia benefits in patients receiving allogenic stem cell transplant.

Allogenic stem cell transplant is the only potentially curative approach for AML patients but has unacceptably high mortality with current treatments, says Florent Gros, co-founder, and CEO of Priothera.

Florent Gros further adds, We are excited about mocravimod which has a unique mechanism of action and clinical proof of concept demonstrating its ability to improve survival outcomes for this devastating disease.

Acute myeloid leukemia (AML) is an aggressive and highly proliferative form of cancer where the bone marrow generates abnormal myeloblasts (a type of white blood cell). According to the company, AML is the most common form of leukemia in adults and can metastasise quickly if left untreated. This can typically lead to death within a few months of diagnosis.

Priothera has acquired rights to a drug called mocravimod from Japans Kyorin Pharmaceutical for the treatment of acute myeloid leukaemia.

According to the company, Mocravimod has already been extensively tested in multiple immunologic indications and has shown a survival benefit in an early clinical study evaluating acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) patients undergoing hematopoietic stem cell transplantation (HSCT).

Priothera is developing mocravimod in AML with the aim of enhancing the curative potential of Hematopoietic Stem Cell Transplantation (HSCT). The company claims that promising early clinical results have revealed that mocravimod has the potential to rebalance the patients immune system by decoupling Graft-versus-Host Disease (GvHD) from Graft-versus-Leukemia (GvL), preventing the first and preserving the latter.

Following the closing of the financing, people who have joined the Board of Directors include Florent Gros (Priotheras co-founder and CEO), Dr. Dhaval Patel (Priotheras co-founder and CSO at UCB), Dr. Manus Rogan (Fountain Healthcare Partners co-founder and MD), Dr. Marten Steen (partner at HealthCap), Dr. Henry Skinner (senior vice president at Tekla Capital Management, LLC) and Lionel Carnot (partner at EarlyBird Venture Capital).

Image credits: Jarun Ontakrai/ShutterStock

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AUSTIN, Texas, Oct. 13, 2020 /PRNewswire/ --Direct Biologics, LLC, announced today that the FDA has granted expanded access for ExoFlo in the treatment of patients with COVID-19 associated acute respiratory distress syndrome (ARDS).

While Direct Biologics is already enrolling patients in EXIT COVID-19, its national multi-center, Phase II, placebo controlled, randomized clinical trial, the new expanded access protocol will make ExoFlo available to a broader group of patients with severe COVID-19, many of whom would not meet acceptance criteria for EXIT COVID-19, often under conditions of "compassionate use."

Co-Founder and Chief Executive Officer, Mark Adams, states, "The FDA's approval of expanded access for ExoFlo signifies a critical milestone in the development of advanced treatment for COVID-19 associated illnesses including ARDS. We are excited to be able to provide our product to patients with ARDS associated with COVID-19 in critical need of treatment."

"Amid a potential surge in new COVID-19 cases moving into the fall and winter seasons, this approval could not have come at a better time," notes Joe Schmidt, Co-Founder and President. "Our team is working hard to advance our Phase II EXIT COVID-19 trial to offer additional treatment options."

"Approval of our expanded access protocol offers an option for doctors to administer ExoFlo as a treatment to reverse disease progression, extending hope to COVID-19 patients who are not responding favorably to standard of care," states Chief Medical Officer, Vik Sengupta, MD. "We at Direct Biologics are grateful for every opportunity to help these additional patients in need."

Also in attendance was Congressman Michael McCaul who commented, "I am thrilled to hear a local company from Austin, Texas, has been approved for Expanded Access IND by the FDA. Their product, ExoFlo, will help treat COVID-19 patients who are at risk of severe respiratory infection, which often leads to life-threatening circumstances. Direct Biologics, with support of the FDA, will bring high-class treatments and services to Americans who need them the most."

This approval comes on the heels of multiple approvals for single patient Emergency Investigational New Drug (eIND) applications granted in September and October. Emergency INDs are a mechanism by which physicians can obtain rapid approval to administer medication to a single patient through a direct appeal to the FDA.

About ExoFlo ExoFlo is an investigational new drug that has not been approved or licensed by FDA. It is an extracellular vesicle product isolated from human bone marrow mesenchymal stem or stromal cells (MSCs). ExoFlo provides natural bioactive signals that have been shown to modulate inflammation and direct cellular communication.

About Direct Biologics Direct Biologics, LLC, is headquartered in Austin, Texas, with a recently expanded R&D facility located at the University of California, and an Operations and Order Fulfillment Center located in St. Louis, Missouri. Direct Biologics is a market-leading innovator and cGMP manufacturer of regenerative medical products, including a robust line of extracellular vesicle-based biological products. The Company was created to expand the science of regenerative healing by delivering cutting-edge biologic technologies. Direct Biologics' management team holds extensive collective experience in biologics research, development, and commercialization, making the Company a leader in the evolving, next generation segment of the biotherapeutics industry. Direct Biologics is dedicated to pursuing additional clinical applications of its extracellular vesicle biologic products through the FDA's investigational new drug application process. For more information visit http://www.directbiologics.com.

Phone:1-800-791-1021Email:[emailprotected]

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To keep you healthy from day to day, your body has its own in-built, germ-fighting network.

This network is also known as the lymphatic system, made up of different vessels and organs in your body, from the lymph nodes to the bone marrow. Lymphoma is the name of the cancer that affects this system.

There are many types of lymphoma but Diffuse Large B-Cell Lymphoma (DLBCL) is the most common aggressive type of non-Hodgkin lymphoma, affecting the B-lymphocytes that produce antibodies which help your body fight infections.

According to the World Health Organizations guidance on classifying tumours, DLBCL accounts for 30 to 40 per cent of newly diagnosed cases of non-Hodgkin lymphoma globally.1

In Singapore, Dr Daryl Tan Chen Lung, who specialises in haematology and practises at Mount Elizabeth Hospitals, estimates that lymphoma is the fifth most common cancer in Singapore.2

Unlike other cancer patients, DLBCL patients hardly have any contributing factors to the development of the condition not even hereditary ones though people with existing HIV infections are more prone to getting DLBCL.

As a result of this, and also because lymphoma is less common than other cancers like breast or lung cancer, regular medical check-ups do not test for its genetic indicators. Instead, patients seek medical help only when they spot early symptoms, says Dr Tan. A growing awareness of lymphoma World Lymphoma Awareness Day takes place on Sept 15 each year and better diagnostics measures have led to much earlier detection of the cancer today, compared to a decade ago.

Dr Tan says that early symptoms of DLBCL include lumps in the neck or groin. Sometimes, other organs like the spleen and bone marrow can be affected. However, some patients show no obvious symptoms beyond abdominal pain, fever and loss of weight. It is thus especially important to seek medical attention should you display any of the common symptoms of lymphoma including swollen lymph nodes in the neck, armpit or groin, a persistent fever, excessive night sweats and unexplained weight loss.

Dr Tan adds that the median age of DLBCL patients in Singapore is 60 to 65, though a very small number of patients in their 20s are diagnosed with a subtype of the cancer known as primary mediastinal B-cell lymphoma.

While DLBCL is an aggressive cancer, the good news is that it is highly treatable in the early stages.

Current therapies for treating first-line DLBCL include chemotherapy, chemo-immunotherapy a combination use of chemotherapy and immunotherapy and stem cell transplant in certain groups of patients. About six in 10 of these patients will respond to their treatment3 and not suffer a relapse within the next five years.

This has a huge impact on younger patients who are then able to resume their daily life and go back to work, for example.

Dr Tan remembers a female patient in her early 20s whose career was just taking off. She was admitted with fever and breathlessness. After performing scans on her, it was discovered that there was fluid surrounding her heart and lungs, and she had a tumour in her chest the size of a rugby ball.

Fortunately, because the cure rate for DLBCL is high, the patients condition has since gone into remission.

A combination of chemo-immunotherapy drugs is commonly recommended as a first-line treatment in DLBCL. Radiation therapy or stem cell transplant can also be included as part of the treatment.

However, about four in 10 patients may not eventually respond to these therapies or suffer from a relapse.3 When this happens, treatment options are limited. Some patients can undergo a stem cell transplant, but about half of them are not eligible.4 This group includes older patients with compromised immune systems.

While affected patients can consider continuing with chemotherapy and chemo-immunotherapy, there are new promising treatment options on the horizon, including targeted therapies such as CAR T-cell therapy. These targeted therapies involve using the patients own immune cells also known as T cells or molecules that bind a chemotherapy agent to an antibody to fight cancerous blood cells.

Beyond that, there are also treatment options known as combination therapy. Previously, patients suffering a relapse have had to rely on existing, first-line treatment, which may or may not be effective in combating the cancer. Combination therapy uses the collective effect of different medications to target different areas of cancerous B-cells and destroy them.

Says Dr Tan: [The medical community is] seeing progress in DLBCL immunotherapy. The current cure rate is about 70 per cent. Hopefully, we can increase the number to 80 per cent or more. But we mustnt rest on our laurels as we hope to focus on the 20 per cent of patients who still dont respond to any treatments.

For more information on lymphoma and treatment options, please speak to your healthcare specialist.

1. Lyon, France. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. IARC Press; 2008.2. SingHealth. (n.d). Lymphoma. Retrieved on 30 Sept 2020. (https://www.singhealth.com.sg/patient-care/conditions-treatments/lymphoma)3. Maurer, MJ et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol. 2014; 32: 1066-73.4. Gisselbrecht C, Van Den Neste E. How I manage patients with relapsed/refractory diffuse large B cell lymphoma. Br J Haematol. 2018;182:633643.

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Lymphoma: Higher rates of survival on the horizon - The Straits Times

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Using a brush or comb, in the shower, passing your hand through your hair In a 2015 IFOP survey, three out of four French people (76%) without baldness declared that they lost their hair. In addition, after 65 years, three in ten men suffer from androgenetic alopecia (or baldness). In general, therefore, we often see a loss of density with age, both in men and in women. However, science has long looked into the phenomenon of age-related hair loss, both to understand its origin and to treat it. Focusing on stem cells seems to offer the best hope for a cure, based on numerous studies.

The hair transplant procedure is indeed a sometimes expensive and invasive procedure. As for drugs, finasteride used for androgenetic alopecia in men can induce side effects such as loss of libido and erectile dysfunction while minoxidil can cause hypertrichosis. Today, researchers therefore seem to be looking more at alternative solutions, and in particular by focusing on stem cells.

Stem cells, directly linked to hair lossFor decades, researchers have always focused on keratinocytes, cells that make up the epidermis and integuments (body hair, hair, etc.). However, as part of a study conducted by the University of Calgary (Canada), the team of researchers focused on a small cell group present in hair follicles and in skin stem cells. : fibroblasts. And according to them, these fibroblasts are the main cause of age-related hair loss.

By studying the sparse coat of elderly mice, they noticed that fibroblast stem cells had lost their regenerative function or were malfunctioning. There werent enough of them to regenerate fibroblasts. As a result, the fibroblasts and hair follicles began to miniaturize and were no longer able to produce hair, explains Biernaskie, head of the research team.

Remember that fibroblasts are important because they send messages to keratinocytes to force them to divide, and in so doing, orchestrate the growth cycles of hair follicles allowing the production of new hairs. When the fibroblasts become scarce, the signal then becomes too weak to reach the keratinocytes and maintain the process of capillary growth. For Jeff Biernaskie: if we want to one day succeed in preventing hair loss or re-grow those that are already falling, we must work to preserve the function of these stem cells which are found in the hair follicles.

Against hair loss, but not only!This finding may help guide future research on hair loss more precisely. Scientists at the University of Calgary are particularly hoping to find a way to prevent this degeneration by blocking certain genetic mutations that occur directly in stem cells in fibroblasts.

They also believe that this will have wider implications. Indeed, Wisoo Shin, lead author of the study, points out that similar fibroblasts are found in most of our organs, maintaining their integrity and promoting tissue regeneration. Finding a way to promote self-renewal to produce new functional fibroblasts into old age therefore also offers the hope of being able to treat certain injuries and help the skin to regenerate.

Lamia spent a couple of years interning at an organization that offered medical consultation before joining the editorial team at FLWL News. An enthusiastic fitness freak in the room, she offers the best amounts of insights and craft-based writing style to keep us up to date about the medicine industry, health and science.

Email:lamia@flwl.orgPhone: +1 512-845-8162

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Electric organoid: Neurons derived from people with 22q11.2 syndrome are hyperexcitable and show calcium-signaling deficits.

Courtesy of Pasca lab

Neurons derived from people with 22q11.2 deletion syndrome, a genetic condition linked to autism, show deficits in electrical activity and calcium signaling, according to a new study1. A single gene appears to be largely responsible for these defects, the study shows.

Up to 20 percent of people who lack part or all of the chromosomal region 22q11.2 have autism. Individuals with the deletion may also have schizophrenia, seizures, heart defects, immune dysfunction or learning problems.

The new findings uncover factors that may contribute to the development of psychiatric conditions associated with 22q11.2 deletion syndrome. They could also help researchers identify new therapeutic targets, says lead author Sergiu Pasca, associate professor of psychiatry and behavioral sciences at Stanford University in California.

The syndrome is relatively common, occurring in up to 1 in 4,000 newborns, Pasca says. But researchers do not fully understand how genes in the 22q11.2 region contribute to autism or other conditions, he adds.

To solve this molecular puzzle, Pasca and his team reprogrammed skin cells from 15 people with the deletion and 15 controls into induced pluripotent stem cells. Using a technique they developed in 2015, they coaxed these cells to turn into neurons, which self-organize in a dish into spherical clusters called organoids. The organoids show some key features of the developing cerebral cortex, a brain region implicated in autism.

The neurons derived from people with 22q11.2 syndrome spontaneously fire four times as frequently as neurons derived from controls, the researchers found. And the electrical activity of the 22q cells does not set off the usual spike in calcium levels, which is crucial for neurons to exchange messages.

In some other syndromes tied to schizophrenia and autism, calcium-channel genes are mutated. But the number of channels and the speed at which they work in 22q neurons is the same as in control neurons. Instead, the 22q cells show an unusually low voltage difference across the cell membrane when they arent firing, causing the signaling defects and hyperexcitability, the researchers found.

The researchers suspected that a gene called DGCR8 might be responsible for the neuronal deficits in the organoids because it lies within 22q11.2 and is linked to abnormal electrical activity in the neurons of mice2. DGCR8 is essential for the synthesis of short RNA fragments, called microRNAs, that regulate gene expression.

Lowering DGCR8s expression levels in control neurons reproduced the abnormalities seen in 22q neurons. In contrast, boosting the genes activity in 22q neurons or treating them with antipsychotic drugs prevented them from being overly excitable and reversed their calcium-signaling defects. The study was published 28 September in Nature Medicine.

Previous studies have analyzed lab-grown neurons derived from people with schizophrenia or autism-related disorders such as Rett and fragile X syndromes. But most used only a few human-derived cell lines, says Guo-li Ming, professor of neuroscience at the University of Pennsylvania in Philadelphia. The new study, Ming says, has a total of 30 human lines thats a huge effort.

By studying brain organoids derived from so many people, the researchers were able to identify the gene that might be involved in the psychiatric conditions associated with 22q11.2 syndrome, says Sally Temple, scientific director of the Neural Stem Cell Institute in Rensselaer, New York. Whenever we have a light shining ahead, saying, This is what you should really be looking at, it means that were making progress, she says.

The study participants with 22q11.2 syndrome vary in their psychiatric diagnoses, and yet all the brain organoids derived from their cells show the same neuronal abnormalities. Thats somewhat surprising, because we know there are a lot of differences in the genetic background of different people, Ming says.

The deletion might conspire with other factors to ultimately determine which psychiatric conditions a person has, Pasca says. It could be that the deletion causes cellular defects, and once there is a stressor such as social stress, disease develops. Its also unclear whether these cellular defects are related to the high prevalence of seizures in people with 22q11.2 syndrome, he says.

The hallmarks of most neuropsychiatric conditions can change over time, says Giuseppe Testa, director of the stem cell epigenetics unit at the European Institute of Oncology in Milan, Italy. Studies that look at a larger number of people with 22q11.2 deletion syndrome or other neurodevelopmental conditions could help to elucidate the relationship between the neuronal defects observed in the lab and the psychiatric manifestations of the conditions, Testa says. The new study, however, is a great resource for understanding how the 22q11.2 deletion contributes to schizophrenia and autism, he says.

Pascas team is trying to pinpoint molecules that could open new therapeutic avenues for 22q11.2 deletion syndrome. The antipsychotics they tested restore the unusual voltage differences in the 22q neurons, but they dont address the core mechanisms responsible for psychiatric conditions linked to the syndrome, Pasca says.

Whats more, antipsychotics have many side effects, and not all individuals respond to them, he says. We need better therapies we need to identify what the key molecular players are and target those.

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When thinking about donating bone marrow, most will break out in a cold sweat.

The thought of needles, prodding and poking is enough to put anyone off from becoming a donor but Ndinae Muligwe, Sustainability and Donor Recruitment Coordinator for the South African Bone Marrow Registry (SABMR) explained that it is a less complicated and relatively painless process.

The SABMR was established in 1991 and is a non-profit organisation that conducts searches to find matching bone marrow donors for critically ill children and adults in South Africa who cannot find a match in their own families.

Bone marrow transplants help to treat and even sometimes cure illnesses like leukaemia, Non-Hodgkin lymphoma, bone marrow failure, and some genetic blood and immune-system disorders.

Ndinae explained that the likelihood of a donor finding a match is about one in 100 000. What is more concerning is that there are currently only around 74 000 local donors on the South African Bone Marrow Registry.

Although they do form part of the World Marrow Donor Association that represents about 38 million donors, there are not enough donors for the South African demographic.

Ethnicity plays a role when it comes to who is able to donate, and at the moment the numbers do not match the ethnic groups represented in South Africa. You are more likely to find a match within your own ethnic group.

But how do you become a donor and what is the process involved?

Ndinae said it is as easy as registering on the website. Of course there are some questionnaires to fill in and you will have to meet the criteria and be healthy.

The donating age has recently been lowered from 18 to 16 years of age, and applicants must be between 16 and 45 to register as a potential donor.

If you are eligible you will then be contacted by the SABMR to do a cheek swab free of charge.

Peripheral blood stem cell (PBSC) collection is the most likely way of collecting stem cells. These cells are found in your bone marrow and also the blood stream. A five-day course of growth factor or Granulocyte-Colony Stimulating Factors is given prior to the donation to encourage the stem cells to move from your marrow to your blood.

At the time of donation a needle is placed in one arm. The blood is then passed through a machine that collects the stem cells, and the remaining blood is returned to your body similar to donating blood platelets.

You do not have to pay for anything to make a tissue or blood donation of your bone marrow stem cells, the SABMR covers the cost of testing and collection.

Visitwww.sabmr.co.zafor more information.

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Embryonic stem cell research has been always disputed by the 2020 Republican party. In 2019, Trumps administration paused funding for government scientists to work on studies involving embryonic stem cells, affecting about $31m in research, according to Science Magazine.

Regeneron, on the other hand, doesnt consider these cells fetal tissue because the HEK-293T line of cells has been immortalized and they divide and regenerate themselves in the laboratory.

The investigational drug has been in clinical trials since June. Even though early results from a trial with around 300 non-hospitalised COVID patients showed the drug was safe and could reduce viral levels and improve symptoms, the data is yet to be peer-reviewed.

According to CNN, the treatment is not yet approved for any use from the US FDA. The company, however, is in talks for an emergency approval. Regeneron has also confirmed that it had provided the drug under a compassionate use request for President Trump from the doctors.

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COVID Drug Given to Trump Developed From Aborted Fetus Cells - Quint Fit

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IRVINE, Calif., Oct. 9, 2020 /PRNewswire/ --AIVITA Biomedical, Inc., a private biotechnology company developing personalized vaccines for the treatment of cancer and COVID-19, announced today the publication of the peer-reviewed manuscript, "Retina organoid transplants develop photoreceptors and improve visual function in RCS rats with RPE dysfunction,"in the journal Investigative Ophthalmology & Visual Science. The study, led by researchers at AIVITA Biomedical and the Sue & Bill Gross Stem Cell Research Center of the University of California, Irvine, used 3D-retina organoids generated from human stem cells developed by AIVITA to provide insight into the potential use of transplanted retina organoids as a therapeutic option for blinding diseases.

In the study, transplanted retina organoid sheets were examined to determine if human stem cell-derived photoreceptors coulddevelop, survive and function in vivo without the support of healthy retina pigment epithelium (RPE). Visual function was examined through a variety of tests, including optokinetic testing (OKT), electroretinogram (ERG), and superior colliculus (SC) brain recording. These tests concluded that retina organoid transplantations demonstrated significant improvement in visual function compared to non-surgery and sham surgery controls, supporting the application of AIVITA's stem cell technologies in visual disease therapeutics.

"Leveraging our expertise in stem cell growth and differentiation, I'm excited to see the promise of our technology platform in potential therapeutics for vision loss," said Hans Keirstead, Ph.D., chief executive officer of AIVITA and a contributing author to the paper. "To our knowledge, this study is the first to show that it's possible for photoreceptors derived from stem cells to survive and function after transplantation when a host has a dysfunctional RPE."

This work is supported by funding from the California Institute for Regenerative Medicine (CIRM) and National Institutes of Health (NIH).

About AIVITA Biomedical AIVITA Biomedical is a privately held company engaged in the advancement of commercial and clinical-stage programs utilizing curative and regenerative medicines. Founded in 2016 by pioneers in the stem cell industry, AIVITA Biomedical utilizes its expertise in stem cell growth and directed, high-purity differentiation to enable safe, efficient and economical manufacturing systems which support its therapeutic pipeline and commercial line of skin care products. All proceeds from the sale of AIVITA's skin care products support the treatment of people with cancer.

SOURCE AIVITA Biomedical, Inc.

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AIVITA Biomedical's Stem Cell Therapeutic in Vision Loss Published in Investigative Ophthalmology & Vision Science - PRNewswire

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Patients with cystic fibrosis experience recurrent lung infections that eventually destroy their airways, shortening their average life expectancy to 50 years in Canada. Current drug treatments, which target a malfunctioning pathway in cells that causes the infections, are costly and have varying effectiveness.

Now, with funding from Medicine by Design, a researcher at the Hospital for Sick Children (SickKids) is combining stem cells, gene editing and computational modelling to try to hijack an alternative cell pathway in the hopes of restoring lung function in these patients.

If successful, our study will be the first to provide proof-of-concept that this alternative approach to treating cystic fibrosis is effective, saysAmy Wong, a scientist working in developmental and stem cell biology at SickKids who is also an assistant professor in the department of laboratory medicine and pathobiology in the University of Torontos Temerty Faculty of Medicine.

Wongs project is one of seven across U of T and its affiliated hospitals that have been awarded 2020New Ideas AwardsandSeed Fundawards from Medicine by Design. Through a $1 million investment, Medicine by Design is supporting research aimed at advancing new concepts expected to be important to regenerative medicine in the coming years. The funded projects will have potential impacts in diseases and conditions such as vision loss, amyotrophic lateral sclerosis (ALS), intestinal disease in premature babies and more.

Supporting novel strategies and approaches is crucial to moving regenerative medicine into the future, saysMichael Sefton, executive director of Medicine by Designand a University Professor at U of Ts Institute of Biomedical Engineeringand thedepartment of chemical engineering & applied chemistry in the Faculty of Applied Science & Engineering.

Our 2020 New Ideas project portfolio integrates mathematical modelling, physics and computational biology with stem cell biology and biomedical engineering, and strengthens engagement with clinicians who are key to translating our research into patient impact. We are particularly delighted this year to support so many outstanding early-career researchers, who will ensure Toronto remains a global leader in regenerative medicine for years to come.

Wong is one of three investigators to receive a 2020 New Ideas Award, which is valued at $100,000 per year for up to two years. Four additional projects were selected for Seed Fund Awards of $100,000 each for one year to further develop their potential.

Medicine by Design selected the funded projects from among 36 short-listed proposals, which were evaluated and ranked through an external peer review process. Applications were submitted by clinicians and researchers at U of T and its affiliated hospitals from a wide range of disciplines including biochemistry, biomedical engineering, developmental and stem cell biology, immunology, neuroscience and surgery.

Medicine by Design builds on decades of made-in-Canada excellence in regenerative medicine dating back to the discovery of stem cells in the early 1960s by Toronto researchers James Till and Ernest McCulloch. Regenerative medicine uses stem cells to replace diseased tissues and organs, creating therapies in which cells are the biological product. It can also mean triggering stem cells that are already present in the human body to repair damaged tissues or to modulate immune responses. Increasingly, regenerative medicine researchers are using a stem cell lens to identify critical interactions or defects that prepare the ground for disease, paving the way for new approaches to preventing disease before it starts. Medicine by Design is made possible thanks in part to a $114-million grant from theCanada First Research Excellence Fund.

Current cystic fibrosis drug treatments target a genetic mutation that causes epithelial cells, which line the airway and act as a barrier against viruses, to function improperly. The mutation affects the function of an important ion channel in cells, called CFTR, which helps to maintain the right balance of fluid in the airways. Poor function causes mucosal obstructions in the airways and prevents clearance of foreign pathogens, which leads to chronic infections and ultimately destroys airway tissue.

In her project, Wong will explore an alternative ion channel in the epithelial cells to determine if it can be hijacked and used to compensate for the lack of function caused by the mutant CFTR. The research will be conducted using a combination of stem cell-derived lung models, gene editing and computational modelling.

Wongs project builds on decades of cystic fibrosis research at SickKids, where the cystic fibrosis gene was first identified 30 years ago.

To date, more than 2,000 mutations in the cystic fibrosis gene have been identified, says Wong. SickKids scientists and U of T researchers have become the epicentre of incredible cystic fibrosis research to understand how this disease works at the genetic and molecular level.

Wong says that, while the idea of targeting an alternative pathway is not necessarily ground-breaking on its own, its the array of tools now available that makes the idea a potential game changer.

We have access to an incredible resource of primary cells and stem cells from more than 100 individuals with cystic fibrosis harbouring various mutations. Wong says.Our lab has developed human lung models from stem cells that can be used to model lung disease such as cystic fibrosis. And with new advanced tools in single-cell genomics and gene-editing, coupled with key collaborations for computational modelling, we are poised to find new therapeutic targets for cystic fibrosis.

Leo Chou, an assistant professor at the Institute of Biomedical Engineering, andHyun Kate Lee, an assistant professor in the department of biochemistry in the Temerty Faculty of Medicineboth Medicine by Design New Investigators are also leading 2020 New Ideas projects.

Chou, along with co-investigatorsJulie Lefebvre, a scientist at SickKids and U of T assistant professor of molecular genetics, andValerie Wallace, a senior scientist at the Krembil Research Institute, University Health Network and a U of T professor of laboratory medicine and pathobiology and ophthalmology, will focus on cell transplantation in the retina, a process that has demonstrated encouraging pre-clinical results such as partial vision restoration in several animal disease models.

Recent research had demonstrated that this restoration is a result of the transfer of proteins complex molecules required for the structure, function and regulation of the bodys tissues between host tissue and donor cells. But the scope of that transfer process is not well understood. Chous project will develop an imaging approach to detect the transfer of mRNA molecules between host and donor cells. The outcomes from this project will inform the future design of cell transplantation therapies and lead to novel methods to deliver therapeutics. This project could improve therapies for retinal diseases and visual impairments, and inform strategies for other degenerative disorders.

Lee and co-investigatorPenney Gilbert,an associate professor at the Institute of Biomedical Engineering, will look at a common but not well-understood structure called the neuromuscular junction (NMJ), which mediates communication between neurons and muscles throughout the body. Defects in NMJ integrity and function underlie fatal diseases such as ALS. NMJ diseases, which affect more than 500,000 people globally, lack effective treatments. This project will use stem cells derived from reprogrammed skin cells of healthy people to develop NMJs in culture. Through high-resolution imaging, the healthy human NMJs will be studied both on their own and along with NMJs built from ALS patient cells. Through this work, the research team aims to identify genes to target to improve the health of NMJs, which could eventually help prevent or delay NMJ degeneration and even promote regeneration.

Michael Garton, an assistant professor at the Institute of Biomedical Engineering, has received a Seed Fund award to tackle the challenge of translating the genetic tools of synthetic biology an area of research that aims to create or redesign biological components using engineering methods into effective medical therapies against a number of diseases.

But they are difficult to translate into human therapies, Garton says, because the bodys T-cells immune cells that detect and destroy cells containing foreign material will identify these tools as foreign and destroy them.

Instead of switching off the T-cells, Gartons goal is to use computational modelling and high-throughput screening to selectively turn off the bodys foreign antigen display system so the immune system will still respond to foreign invaders when necessary, but allow cells containing synthetic tools to survive. If successful, this approach could enable a new generation of synthetic biology-enhanced cell therapies for a range of diseases.

Medicine by Design funding will help to facilitate the integration of synthetic biology and regenerative medicine and aid the development of cell-based therapies that perform better than nature, says Garton.

Other Seed Fund projects will encompass research in repairing the heart after paediatric cardiac surgery, treating an intestinal emergency in premature babies and creating a database for cell lineage paths.

John Parkinson, a senior scientist at SickKids and a U of T professor of biochemistry and molecular genetics, along with co-investigatorsJason Maynes, Wasser Chair in Anesthesia and Pain Medicine at SickKids and a U of Tassociate professor of anesthesiology and biochemistry, andWilliam Navarre, an associate professor in the department of molecular genetics, will investigate manipulating the microbiome, or community of microorganisms in the gut, to improve cardiac repair in post-operative treatment of a congenital heart disorder. Through a process that will identify prebiotics in breast milk that help enhance the production of molecules that research has shown can aid cardiac repair, the team will organize both observational (how disease alters the microbiome) and interventional (how the microbiome alters the disease) multi-site trials, which will provide the opportunity to immediately translate findings into changes in patient care regimens and improve outcomes.

CliniciansAgostino Pierro, a surgeon at the Division of General and Thoracic Surgery at SickKids and a U of T professor of surgery and physiology, and Philip Sherman, a senior scientist and gastroenterologist at the Division of Gastroenterology, Hepatology and Nutrition at SickKids and U of T professor of dentistry, pediatrics and laboratory medicine and pathobiology, have proposed a novel way of enhancing gut repair for a common intestinal emergency in premature babies, called necrotizing enterocolitis (NEC). A leading cause of death for these infants, NEC causes complications such as blindness, intellectual disability, repeat hospitalizations and gut damage even in those that survive. This project will look at whether intestinal organoids organ-like structures grown in the laboratory from stem cells that mimic some of the functions of native intestines can potentially stimulate repair of the gut and recovery from NEC. The project will define how to best transplant organoids, identify how the organoids protect the intestine from injury and assess if organoid transplantation is a valid new treatment for NEC.

Lincoln Stein, who is head of adaptive oncology at the Ontario Institute for Cancer Research and a professor in the department of molecular genetics at U of T, has received seed funding to build a database called Cytomics Reactome, which will be freely available to Canadian and international researchers. The database will build on recent technologies that open the door to the possibility of deciphering cell lineage paths the series of steps that lead a young, undifferentiated cell into a specialized one at single-cell resolution. To accelerate the path from basic research to clinical application, the database will systematically organize pre-existing knowledge of cell lineage paths into a comprehensive, interactive and easily accessible map that can serve as a framework for interpretation and integration of the latest experimental findings.

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U of T's Medicine by Design invests $1 million to advance new ideas in regenerative medicine - News@UofT

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