Do Therapies for Alzheimer’s & Parkinson’s that Clear Abnormal Brain Proteins Make the Diseases Worse? – BioSpace
By daniellenierenberg
One of the common research approaches to treating brain diseases such as Parkinsons disease (PD) and Alzheimers disease (AD) is using antibodies designed to clear the accumulated misfolded proteins implicated in the diseases. To date, these drug trials have not been particularly successful at improving the disease, even when they are effective at removing the proteins. A new theory hypothesizes that the antibodies are actually increasing the neuroinflammation associated with PD and AD, basically making the disease worse while removing the proteins.
Stuart Lipton, a researcher at Scripps Research Institute, recently published research suggesting that this may be exactly what is happening. They ran a series of in vitro assays and experiments in mice that had brain grafts of human-induced pluripotent stem cell (hiPSC)-derived microglia (hiMG). They found that the antibodies that target the misfolded proteins found in PD and AD trigger the NLRP3 inflammasome, which can lead to cell death.
Our findings provide a possible explanation for why antibody treatments have not yet succeeded against neurodegenerative diseases, said co-senior author Lipton, Step Family Foundation endowed chair in the department of molecular medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research.
The results were published in Proceedings of the National Academy of Sciences (PNAS).
The research started when Dorit Trudler, a postdoctorate researcher in Liptons lab, attempted to make microglia in the lab. Microglia are the innate immune cells in the brain, and it is a notoriously difficult task because the cells dont originate from the same type of stem cells in the bone marrow that generates the rest of the immune system.
Instead of coming from the bone marrow like B and T cells and macrophages, microglia are created from the yolk sac that embryos swim in during early development, then migrate from the sac to the brain. Trudler was able to turn human-derived stem cells to turn into a yolk sac-like structure, and from there, developed cells that were identical to microglia removed from humans based on the mRNA they expressed.
Lipton indicated, They match as closely as possible.
They then exposed these microglia to either alpha-synuclein, the misfolded protein identified in Parkinsons patients, and the microglia shot off inflammatory signals. And when they exposed the microglia to amyloid-beta, the hallmark of Alzheimers, the inflammation grew worse.
They then worked with biopharma companies to obtain antibodies that bind to either alpha-synuclein or amyloid-beta. Although Lipton is not saying which companies, it did say one of them was not Biogens aducanumab, which is up for approval or rejection for Alzheimers by June 7 by the U.S. Food and Drug Administration (FDA).
The surprising and potentially extremely important result was that although the antibodies successfully attached to their protein targets, it didnt help with inflammation. Rather than make things better, it actually made things worse, Lipton said.
And they further found in humanized mice with both human and mice microglia, that the pro-inflammatory response was unique to the human cells. This means that biopharma companies, in working with laboratory animals on therapeutic antibodies for these diseases, would not have seen this reaction. Although unclear yet why its causing inflammation, they are convinced the NLRP3 pathway is involved, although they dont have the exact mechanism worked out. Potentially, however, it might be possible to treat patients with a combination of the protein-clearing drugs and anti-inflammatories that block the NLRP3 pathway.
In an unrelated study, researchers at Massachusetts General Hospital utilized whole-genome sequencing (WGS) to identify rare genomic variants associated with AD. In doing so, they found 13 mutations, which establish new genetic links between AD and synaptic function. They believe it could help guide the development of new drugs for AD.
The first group of genes identified that were associated with AD involve the accumulation of amyloid-beta. The next 30 AD gene mutations identified were linked to chronic inflammation in the brain. Loss of synapses is the neurological change most closely linked with the severity of dementia in AD, but until now clear genetic association had not been identified.
Rudolph Tanzi, vice chair of Neurology and director of the hospitals Genetics and Aging Research Unit, said, It was always kind of surprising that whole-genome screens had not identified Alzheimers genes that are directly involved with synapses and neuroplasticity.
Tanzi went on to note that identifying less-common mutations that increase the risk for AD may provide critical information about the disease. Rare gene variants are the dark matter of the human genome, he said.
There are many of them, as it turns out. Of the three billion pairs of nucleotide bases in the human genome, about 5o to 60 million are gene variants and 77% are rare.
- A pilot raced through the airport to surprise an old friend: the woman who saved his life - CNN - December 27th, 2024
- Types of Stem Cell and Bone Marrow Transplants - December 27th, 2024
- Explained: What is mesenchymal stem cell therapy? - Drug Discovery News - December 18th, 2024
- Stem Cell Transplants Offer New Hope for Saving the Worlds Corals - Technology Networks - December 18th, 2024
- Scientists Present Research on Novel Cancer Therapies at ASH - City of Hope - December 18th, 2024
- Navigating CAR-T cell therapy long-term complications - Nature.com - December 18th, 2024
- High-dose chemotherapy followed by autologous stem cell transplant ineffective for patients with mantle cell lymphoma - News-Medical.Net - December 18th, 2024
- Stem Cell Therapy Market Is Expected To Reach Revenue Of - GlobeNewswire - December 18th, 2024
- The Importance of Cellular Therapy in the Clinical Case of a Young Man With a Challenging Precursor B-cell Lymphoblastic Leukemia - Cureus - December 18th, 2024
- A search for the perfect match, Apex six year old in need of donor - CBS17.com - December 18th, 2024
- New insights into survival of breast cancer cells in the bone marrow - News-Medical.Net - December 9th, 2024
- Cellular trafficking and fate mapping of cells within the nervous system after in utero hematopoietic cell transplantation - Nature.com - December 9th, 2024
- Saving lives, one stem cell at a time - Texas A&M The Battalion - December 9th, 2024
- Turn Biotechnologies Announces Landmark Study to Assess Effectiveness of ERA Therapy in Restoring Bone Marrow - PR Newswire UK - December 9th, 2024
- Orca Bio Presents Three-Year Survival Data with Orca-T in Patients with Hematological Malignancies at the 66th ASH Annual Meeting - Yahoo Finance - December 9th, 2024
- You are the match. How UNC student honored her late grandfather with life-saving effort - Raleigh News & Observer - November 29th, 2024
- scRNA-seq revealed transcriptional signatures of human umbilical cord primitive stem cells and their germ lineage origin regulated by imprinted genes... - November 29th, 2024
- Atlanta pilot with an aggressive cancer finds lifesaving help from a stranger and a simple test - The Atlanta Journal Constitution - November 29th, 2024
- Researchers have brought the promise of stem cell therapies closer to reality - The Week - November 29th, 2024
- Bone Marrow Donors Can Be Hard to Find. One Company Is Turning to ... - November 15th, 2024
- Hematopoietic Stem Cells and Their Niche in Bone Marrow - November 15th, 2024
- Bone Marrow Transplant Program - Overview - Mayo Clinic - November 15th, 2024
- Bone Marrow Donors Can Be Hard to Find. One Company Is Turning to Cadavers - WIRED - November 15th, 2024
- More stem cells for sickle cell gene therapy readied with motixafortide - Sickle Cell Disease News - November 15th, 2024
- Skull bone marrow expands throughout life and remains healthy during aging, researchers discover - Medical Xpress - November 15th, 2024
- Adult skull bone marrow is an expanding and resilient haematopoietic reservoir - Nature.com - November 15th, 2024
- Evaluation of standard fludarabine dosing and corresponding exposures in infants and young children undergoing hematopoietic cell transplantation -... - November 15th, 2024
- Stem cells grown in space show super powers but theres a catch - Study Finds - November 15th, 2024
- Getting a Stem Cell or Bone Marrow Transplant - October 21st, 2024
- Acquisition of durable insulin-producing cells from human adipose tissue-derived mesenchymal stem cells as a foundation for cell- based therapy of... - October 21st, 2024
- 1.5 Lakh Indians Register To Save Lives: Join the Mission To Fight Blood Cancer - The Better India - October 21st, 2024
- How Stem Cell and Bone Marrow Transplants Are Used to Treat Cancer - October 13th, 2024
- Stem Cell (Bone Marrow) Transplants - MD Anderson Cancer Center - October 13th, 2024
- Donating Bone Marrow and Stem Cells: The Process and What To Expect - October 13th, 2024
- What to expect as a stem cell or bone marrow donor - October 13th, 2024
- Structural organization of the bone marrow and its role in ... - October 13th, 2024
- Stem cell donor from down the road saved my life after global search - BBC.com - September 23rd, 2024
- Awaiting the call: family hopes to find blood stem cell donor - Claremont Courier - September 23rd, 2024
- Michigan woman one of first in world to successfully receive bone marrow from deceased donor - WDIV ClickOnDetroit - September 23rd, 2024
- Next-generation stem cell transplant: Revolutionizing a lifesaving cancer therapy - The Business Journals - September 23rd, 2024
- Sophie's life was saved by a stranger. Some in her position have an 'unfair' disadvantage - SBS News - September 23rd, 2024
- What Are Leukemia and Lymphoma and How Are They Treated? - LVHN News - September 23rd, 2024
- Giralt on MDS Transplant Timing and Candidacy - Targeted Oncology - September 14th, 2024
- Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets - Nature.com - September 14th, 2024
- A practical guide to therapeutic drug monitoring in busulfan: recommendations from the Pharmacist Committee of the European Society for Blood and... - September 14th, 2024
- ISU researcher blown away by blood cell replication discovery - Radio Iowa - September 14th, 2024
- Pausing biological clock could give boost to lab-produced blood stem cells - Phys.org - September 14th, 2024
- 9-year-old gets successful bone marrow transplant - The Times of India - September 14th, 2024
- Dr. Crandall: Stem Cell Treatment Heals the Heart - Newsmax - September 3rd, 2024
- Orion Corporation: Managers’ transactions – Hao Pan - August 19th, 2024
- BioCorRx Reports Business Update for the Second Quarter of 2024 - August 19th, 2024
- Tevogen Bio Reports Second Quarter 2024 Financial Results, Eliminates Doubt About Company’s Ability to Continue as a Going Concern, Eliminates... - August 19th, 2024
- Aligos Therapeutics Announces Reverse Stock Split - August 19th, 2024
- Lumos Pharma to Participate in H.C. Wainwright 26th Annual Global Investment Conference - August 19th, 2024
- Protect Pharmaceutical Corp. (PRTT) Announces New CEO and New Director; Moves to Finalize the Karinca Logistics Merger - August 19th, 2024
- OKYO Pharma Participates in H.C. Wainwright 4th Annual Ophthalmology Virtual Conference - August 19th, 2024
- CORRECTION – Tevogen Bio Reports Second Quarter 2024 Financial Results, Eliminates Doubt About Company’s Ability to Continue as a Going Concern,... - August 19th, 2024
- NurExone Biologic Achieves Key Milestone in Support of Robust Exosome Manufacturing Process - August 19th, 2024
- Silexion Therapeutics Ltd. and Moringa Acquisition Corp Announce Closing of their Business Combination - August 19th, 2024
- Vericel Announces FDA Approval of NexoBrid for the Treatment of Pediatric Patients with Severe Thermal Burns - August 19th, 2024
- Codexis Publishes FY2023 Sustainability Disclosures - August 19th, 2024
- MediWound Announces U.S. Food and Drug Administration Approval of NexoBrid® for the Treatment of Pediatric Patients with Severe Thermal Burns - August 19th, 2024
- First Successful Paediatric Allogeneic Bone Marrow Transplant In Bengaluru; Know All About The Procedure - Onlymyhealth - August 4th, 2024
- Is Stem Cell Transplant Often The Only Treatment Option For Blood Cancer Patients? Why So? - News18 - June 2nd, 2024
- This Swedish startup wants to reduce the cost, and controversy, around stem cell production - TechCrunch - March 10th, 2024
- Bone Marrow Transplantation | Johns Hopkins Medicine - December 20th, 2023
- Mansour bin Zayed witnesses inauguration of ADSCC Bone Marrow Transplant & Cellular Therapy Congress 2023 - ZAWYA - November 26th, 2023
- ADSCC Bone Marrow Transplant and Cellular Therapy Congress 2023 to take place in Abu Dhabi - ZAWYA - November 18th, 2023
- Orchard Therapeutics Reports First Quarter 2023 Financial Results and Announces Initiation of Rolling Submission for Biologics License Application of... - May 16th, 2023
- Family of 7-month-old in need of bone marrow transplant hosting donor registration event - CBS Pittsburgh - May 8th, 2023
- Anika Continues to Expand Addressable Market for Tactoset Injectable Bone Substitute with Additional 510(k) Clearance from FDA - Marketscreener.com - April 5th, 2023
- MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023 -... - April 5th, 2023
- VOR BIOPHARMA INC. Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-K) - Marketscreener.com - March 25th, 2023
- BioRestorative Therapies to Seek FDA Approval to Expand the Clinical Application of BRTX-100 - Marketscreener.com - March 17th, 2023
- BioSenic delivers a new post-hoc analysis of its Phase III JTA-004 trial on knee osteo-arthritis with positive action on the most severely affected... - March 17th, 2023
- JASPER THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com - March 9th, 2023
- For a range of unmet medical needs, India offers a fantastic opportunity to push cell and gene therapies: B .. - ETHealthWorld - March 9th, 2023
- NGM BIOPHARMACEUTICALS INC Management's Discussion and Analysis of Financial Condition and Results of Operations. (form 10-K) - Marketscreener.com - March 1st, 2023
- Bone health: Tips to keep your bones healthy - Mayo Clinic - January 27th, 2023
- Bone marrow drive held for military wife with cancer - January 27th, 2023