Our initial application established the goals of our project and the reasons for our study. Arthritis is the result of degeneration of cartilage (the tissue lining the joints) and leads to pain and limitation of function. Arthritis and other rheumatic diseases are among the most common of all health conditions and are the number one cause of disability in the United States. The annual economic impact of arthritis in the U.S. is estimated at over $120 billion, representing more than 2% of the gross domestic product. The prevalence of arthritic conditions is also expected to increase as the population increases and ages in the coming decades. Current treatment options for osteoarthritis are limited to pain reduction and joint replacement surgery. Stem cells have tremendous potential for treating disease and replacing or regenerating the diseased tissue. In this project our objective is to use cells derived from stems cells to treat arthritis. We have completed our experiments as per our proposed timeline and have met milestones outlined in our grant submission. We have established conditions for converting stem cells into cartilage tissue cells that can repair bone and cartilage defects in laboratory models. We have identified several cell lines with the highest potential for tissue repair. We optimized culture conditions to generate the highest quality of tissue. In our initial experiments we found no evidence of cell rejection response in vivo. We have testing efficacy of the most promising cell lines in regenerating healthy repair tissue in cartilage defects and have selected a preclinical candidate.The next step is to plan safety and efficacy studies for the preclinical phase, identify collaborators with the facilities to obtain, process, and provide cell-based therapies, and identify clinical collaborators in anticipation of clinical trials. If necessary we will also identify commercialization partners. We also anticipate that stem cells implanted in arthritic cartilage will treat the arthritis in addition to producing tissue to heal the defect in the cartilage. An approach that heals cartilage defects as well as treats the underlying arthritis would be very valuable. If our research is successful, this could lead to first treatment of osteoarthritis that alters the progression of the disease. This treatment would have a huge impact on the large numbers of patients who suffer from arthritis as well as in reducing the significant economic burden created by arthritis.

Read more:
Stem Cell-Based Therapy for Cartilage Regeneration and ...

The following was written withProf. Gerold Riempp, a professor of information systems who was diagnosed with Parkinsons disease 16 years ago at age 36. He is co-founder of a charitable organization in Germany that supports the development of therapies that aim to cure PD.

The idea behind cell replacement therapy(CRT) for PD is pretty simple: lack of mobility in PD is the result of the dysfunction and death of a specific kind of cell in the midbrain. While there are a few other things that go wrong in PD, the progressive loss of motor skills is the biggest problem most diagnosed face. Since we are reasonably sure that this lack of mobility results from the impairment and death of dopamine producing cells in an area of the midbrain called the substantia nigra,why not try to replace those cells?

A group of iPS cells grown from human skin tissue at Osaka University

Replacing those cells is one of three core problems that each person diagnosed with PD needs to address. They are:

1. Keeping remaining cells healthyOnce diagnosed, most people have already lost production of 50-80% of dopamine in their midbrain. The problem then is to stop further disease progression by figuring out how to get rid of everything that might be harming the remaining 20-50% of cells while giving their body everything it needs to keep those cells alive and active.

2. Clearing clogged cellsOf those 50-80% of non-dopamine producing cells, a portion are still alive, they are just not doing their job, producing dopamine. This impairment is a result of a range of interrelated factors that harm the cells and eventually lead to their death. Most researchers believe the problem can be boiled down to the clumping of a misfolded protein called alpha-synuclein. Many different methods are being tried in labs around the world to clear these clumps and stop more from accumulating. But this might only be part of the story since a wide variety of other factors also lead to cell death.

3. Replacing dead cellsThen we come to what to do about all of those dead cells. A couple of different options are being considered to get the brain tostimulate the production of new neurons orreplace the function of dead ones. However, the most promising therapy being developed is stem cell therapy, now commonly referred to as cell replacement therapy. It works by placing new dopamine producing neurons into the part of the brain where the dead neurons used to release dopamine.

If a patient manages to address problems one and two they might have no need for CRT. The reason for this is that he or she can likely rescue a considerable portion of the damaged but still living cells and thereby bring dopamine production back to a level that allows for normal movement. CRT will generally be for people who have had PD for a longer time and whose remaining healthy cells plus the rescued ones together are not capable of providing enough dopamine.

The late 80s and 90s saw a number of CRT trials for Parkinsons disease with mixed results. But we nowhave a much better understanding of what kind of cells to use, how to culture and store those cells, how to implant them, and who this therapy would be best for.

We also now have iPS cells (induced pluripotent stem cells). Discovered in 2006, these are cells that have been chemically reprogrammed, usually from adult skin tissue, back into pluripotent stem cells. (Pluripotent means they are capable of becoming almost any cell in the body). Using these cells for transplantation has two major advantages. One, it eliminates the need for potentially harmful immuno-suppressors. Two, it has none of the ethical issues that come with using fetal stem cells. But iPS cells are much more expensive and technically difficult to produce.

Despite all the progress made, cell replacement therapy is still very controversial and fraught with all sorts of technical issues. Luckily, CRT for PD is one of the only fields of medical science where the top labs around the world are cooperating with each other. An international consortium of labs has come together under a name that sounds like it was ripped out of a Marvel comic, the GForce-PD. Each lab in the GForce-PD aims to bring CRT for PD to clinical trial within the next few years.

Infographic made by PhD neuroscientist Kayleen Schreiber at kayleenschreiber.com

The GForce-PD

New York City Run by Dr. Lorenz Studer out of the Rockefeller research labs in New York City. Dr. Studer pioneered many of the reprogramming techniques being used around the world to convert pluripotent stem cells into dopamine producing neurons. His lab wasrecently announced to be part of a huge funding initiative from Bayer Pharmaceuticals to help speed up development of CRT. Studers lab is aiming to start transplantation of embryonic stem cells in human trials in early 2018.

Kyoto, Japan Dr. Jun Takahashis lab in Kyoto is working on producing several iPS lines for the Japanese population. One advantage they have is the relative homogeneity of Japanese people allows them to use a dozen or so iPS lines for almost everyone in the country. The lab recently made headlines with results from monkey trials that showed human iPS cells graft safely, with no signs of malignant growth, two years after transplantation.

Cambridge, England Dr. Roger Barkers lab has been working on cell replacement therapy for Parkinsons disease for a number of years through the Transeuro project. His lab is pushing forward with more embryonic stem cell transplantations expected to begin in 2020. They also work very closely with the team in Sweden.

Lund, Sweden The lab in Lund has been working on CRT for PD since the 80s and has been part of a number of human trials. The lab is now run by Dr. Malin Parmar whose team has also pioneered many of the techniques used in direct programming that will one day allow researchers to skip the stem cell phase all together and produce dopamine cells directly in the brain.

San Diego, California The team is moving rapidly towards iPS cell transplantation under Dr. Jeanne Loring at the Scripps research center. They are the only lab that uses patients own cells for transplantation. Another unique feature of this lab is that it has been a community funded initiative under theSummit For Stem Cellsfoundation.

(Dr. Roger Barker talking about CRT for PD)

Though there is a lot of excitement building around cell replacement therapy, we need to proceed carefully. The field has potential for setbacks from some of the less rigorous trials being conducted in places like Australia and China where regulatory standards are more lax. Researchers in these areas are already going ahead with trials that do not meet the standards set by the GForce-PD. These have the potential to put a black-eye on all cell replacement therapies.

Also, producing pure batches of dopamine neurons is still a highly technical process that only a few labs in the world are capable of doing safely and effectively. Thankfully a few other labs around the world are joining the efforts of the GForce-PD, such as Dr. Tilo Kunaths lab in Edinburgh, which is working on techniques to better differentiate and characterize the cell lines used for transplantation.

(The pictures above show human embryonic stem cells being differentiated into dopamine cells at days 2, 4 and 7. Courtesy of Dr. Tilo Kunaths lab at the University of Edinburgh)

The Future of Cell Replacement Therapy

These therapies being developed for Parkinsons disease will, in essence, be version 1.0 of CRT. Clinical trials are set to begin next year and the therapy is expected to be widely available to people diagnosed with Parkinsons disease within the next 5-10 years.

Version 2.0 will be CRISPR-modified, disease resistant grafts, with genetic switches to modulate dopamine production and graft size.

Version 3.0 will make use of an emerging field called in vivo direct programming where viruses are inserted into the brain and transform other existing cells into dopamine producing cells.

(Edit: Credit to Dr. Tilo Kunath for correcting versions 2.0 and 3.0)

Dopamine neurons grown from iPS cells at 40 times magnification, from the Gladstone Institute

CRT for PD is one of the most exciting areas of research on the planet. It is a powerful demonstration of the progress we as a species have made in our attempt to gain mastery over the forces of biology.It has the potential to improve the lives of the millions living with PD, and the millions yet to be diagnosed. Once the transplanted cells have connected with their surroundings and start delivering dopamine to the right places, it should allow patients to gradually reduce their medication. Being able to move normally and not deal with the side effects of all the drugs and other therapies is what PD patients around the world are dreaming of.

Click here for more information on the future of cell replacement therapy for Parkinsons disease and the work of the GForce-PD.

And if you want to be part of bringing CRT to the clinic you can do so by supporting organizations like Summit For Stem Cells.

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Cell Replacement Therapy For Parkinsons Disease And The ...

Charles A. Goldthwaite, Jr., Ph.D.

In 2006, researchers at Kyoto University in Japan identified conditions that would allow specialized adult cells to be genetically "reprogrammed" to assume a stem cell-like state. These adult cells, called induced pluripotent stem cells (iPSCs), were reprogrammed to an embryonic stem cell-like state by introducing genes important for maintaining the essential properties of embryonic stem cells (ESCs). Since this initial discovery, researchers have rapidly improved the techniques to generate iPSCs, creating a powerful new way to "de-differentiate" cells whose developmental fates had been previously assumed to be determined.

Although much additional research is needed, investigators are beginning to focus on the potential utility of iPSCs as a tool for drug development, modeling of disease, and transplantation medicine. The idea that a patient's tissues could provide him/ her a copious, immune-matched supply of pluripotent cells has captured the imagination of researchers and clinicians worldwide. Furthermore, ethical issues associated with the production of ESCs do not apply to iPSCs, which offer a non-controversial strategy to generate patient-specific stem cell lines. As an introduction to this exciting new field of stem cell research, this chapter will review the characteristics of iPSCs, the technical challenges that must be overcome before this strategy can be deployed, and the cells' potential applications to regenerative medicine.

As noted in other chapters, stem cells represent a precious commodity. Although present in embryonic and adult tissues, practical considerations such as obtaining embryonic tissues and isolating relatively rare cell types have limited the large-scale production of populations of pure stem cells (see the Chapter, "Alternate Methods for Preparing Pluripotent Stem Cells" for details). As such, the logistical challenges of isolating, culturing, purifying, and differentiating stem cell lines that are extracted from tissues have led researchers to explore options for "creating" pluripotent cells using existing non-pluripotent cells. Coaxing abundant, readily available differentiated cells to pluripotency would in principle eliminate the search for rare cells while providing the opportunity to culture clinically useful quantities of stem-like cells.

One strategy to accomplish this goal is nuclear reprogramming, a technique that involves experimentally inducing a stable change in the nucleus of a mature cell that can then be maintained and replicated as the cell divides through mitosis. These changes are most frequently associated with the reacquisition of a pluripotent state, thereby endowing the cell with developmental potential. The strategy has historically been carried out using techniques such as somatic cell nuclear transfer (SCNT),1,2 altered nuclear transfer (ANT),3,4 and methods to fuse somatic cells with ESCs5,6 (see "Alternate Methods for Preparing Pluripotent Stem Cells" for details of these approaches). From a clinical perspective, these methods feature several drawbacks, such as the creation of an embryo or the development of hybrid cells that are not viable to treat disease. However, in 2006, these efforts informed the development of nuclear reprogramming in vitro, the breakthrough method that creates iPSCs.

This approach involves taking mature "somatic" cells from an adult and introducing the genes that encode critical transcription factor proteins, which themselves regulate the function of other genes important for early steps in embryonic development (See Fig. 10.1). In the initial 2006 study, it was reported that only four transcription factors (Oct4, Sox2, Klf4, and c-Myc) were required to reprogram mouse fibroblasts (cells found in the skin and other connective tissue) to an embryonic stem celllike state by forcing them to express genes important for maintaining the defining properties of ESCs.7 These factors were chosen because they were known to be involved in the maintenance of pluripotency, which is the capability to generate all other cell types of the body. The newly-created iPSCs were found to be highly similar to ESCs and could be established after several weeks in culture.7,8 In 2007, two different research groups reached a new milestone by deriving iPSCs from human cells, using either the original four genes9 or a different combination containing Oct4, Sox2, Nanog, and Lin28.10 Since then, researchers have reported generating iPSCs from somatic tissues of the monkey11 and rat.12,13

However, these original methods of reprogramming are inefficient, yielding iPSCs in less than 1% of the starting adult cells.14,15 The type of adult cell used also affects efficiency; fibroblasts require more time for factor expression and have lower efficiency of reprogramming than do human keratinocytes, mouse liver and stomach cells, or mouse neural stem cells.1419

Several approaches have been investigated to improve reprogramming efficiency and decrease potentially detrimental side effects of the reprogramming process. Since the retroviruses used to deliver the four transcription factors in the earliest studies can potentially cause mutagenesis (see below), researchers have investigated whether all four factors are absolutely necessary. In particular, the gene c-Myc is known to promote tumor growth in some cases, which would negatively affect iPSC usefulness in transplantation therapies. To this end, researchers tested a three-factor approach that uses the orphan nuclear receptor Esrrb with Oct4 and Sox2, and were able to convert mouse embryonic fibroblasts to iPSCs.20 This achievement corroborates other reports that c-Myc is dispensable for direct reprogramming of mouse fibroblasts.21 Subsequent studies have further reduced the number of genes required for reprogramming,2226 and researchers continue to identify chemicals that can either substitute for or enhance the efficiency of transcription factors in this process.27 These breakthroughs continue to inform and to simplify the reprogramming process, thereby advancing the field toward the generation of patient-specific stem cells for clinical application. However, as the next section will discuss, the method by which transcription factors are delivered to the somatic cells is critical to their potential use in the clinic.

Figure 10.1. Generating Induced Pluripotent Stem Cells (iPSCs).

2008 Terese Winslow

Reprogramming poses several challenges for researchers who hope to apply it to regenerative medicine. To deliver the desired transcription factors, the DNA that encodes their production must be introduced and integrated into the genome of the somatic cells. Early efforts to generate iPSCs accomplished this goal using retroviral vectors. A retrovirus is an RNA virus that uses an enzyme, reverse transcriptase, to replicate in a host cell and subsequently produce DNA from its RNA genome. This DNA incorporates into the host's genome, allowing the virus to replicate as part of the host cell's DNA. However, the forced expression of these genes cannot be controlled fully, leading to unpredictable effects.28 While other types of integrating viruses, such as lentiviruses, can increase the efficiency of reprogramming,16 the expression of viral transgenes remains a critical clinical issue. Given the dual needs of reducing the drawbacks of viral integration and maximizing reprogramming efficiency, researchers are exploring a number of strategies to reprogram cells in the absence of integrating viral vectors2730 or to use potentially more efficient integrative approaches.31,32

Before reprogramming can be considered for use as a clinical tool, the efficiency of the process must improve substantially. Although researchers have begun to identify the myriad molecular pathways that are implicated in reprogramming somatic cells,15 much more basic research will be required to identify the full spectrum of events that enable this process. Simply adding transcription factors to a population of differentiated cells does not guarantee reprogrammingthe low efficiency of reprogramming in vitro suggests that additional rare events are necessary to generate iPSCs, and the efficiency of reprogramming decreases even further with fibroblasts that have been cultured for long time periods.33 Furthermore, the differentiation stage of the starting cell appears to impact directly the reprogramming efficiency; mouse hematopoietic stem and progenitor cells give rise to iPSCs up to 300 times more efficiently than do their terminally-differentiated B- and T-cell counterparts.34 As this field continues to develop, researchers are exploring the reprogramming of stem or adult progenitor cells from mice24,25,34,35 and humans23,26 as one strategy to increase efficiency compared to that observed with mature cells.

As these discussions suggest, clinical application of iPSCs will require safe and highly efficient generation of stem cells. As scientists increase their understanding of the molecular mechanisms that underlie reprogramming, they will be able to identify the cell types and conditions that most effectively enable the process and use this information to design tools for widespread use. Clinical application of these cells will require methods to reprogram cells while minimizing DNA alterations. To this end, researchers have found ways to introduce combinations of factors in a single viral "cassette" into a known genetic location.36 Evolving tools such as these will enable researchers to induce programming more safely, thereby informing basic iPSC research and moving this technology closer to clinical application.

ESCs and iPSCs are created using different strategies and conditions, leading researchers to ask whether the cell types are truly equivalent. To assess this issue, investigators have begun extensive comparisons to determine pluripotency, gene expression, and function of differentiated cell derivatives. Ultimately, the two cell types exhibit some differences, yet they are remarkably similar in many key aspects that could impact their application to regenerative medicine. Future experiments will determine the clinical significance (if any) of the observed differences between the cell types.

Other than their derivation from adult tissues, iPSCs meet the defining criteria for ESCs. Mouse and human iPSCs demonstrate important characteristics of pluripotent stem cells, including expressing stem cell markers, forming tumors containing cell types from all three primitive embryonic layers, and displaying the capacity to contribute to many different tissues when injected into mouse embryos at a very early stage of development. Initially, it was unclear that iPSCs were truly pluripotent, as early iPSC lines contributed to mouse embryonic development but failed to produce live-born progeny as do ESCs. In late 2009, however, several research groups reported mouse iPSC lines that are capable of producing live births,37,38 noting that the cells maintain a pluripotent potential that is "very close to" that of ESCs.38 Therefore, iPSCs appear to be truly pluripotent, although they are less efficient than ESCs with respect to differentiating into all cell types.38 In addition, the two cell types appear to have similar defense mechanisms to thwart the production of DNA-damaging reactive oxygen species, thereby conferring the cells with comparable capabilities to maintain genomic integrity.39

Undifferentiated iPSCs appear molecularly indistinguishable from ESCs. However, comparative genomic analyses reveal differences between the two cell types. For example, hundreds of genes are differentially expressed in ESCs and iPSCs,40 and there appear to be subtle but detectable differences in epigenetic methylation between the two cell types.41,42 Genomic differences are to be expected; it has been reported that gene-expression profiles of iPSCs and ESCs from the same species differ no more than observed variability among individual ESC lines.43 It should be noted that the functional implications of these findings are presently unknown, and observed differences may ultimately prove functionally inconsequential.44

Recently, some of the researchers who first generated human iPSCs compared the ability of iPSCs and human ESCs to differentiate into neural cells (e.g., neurons and glia).45 Their results demonstrated that both cell types follow the same steps and time course during differentiation. However, although human ESCs differentiate into neural cells with a similar efficiency regardless of the cell line used, iPSC-derived neural cells demonstrate lower efficiency and greater variability when differentiating into neural cells. These observations occurred regardless of which of several iPSC-generation protocols were used to reprogram the original cell to the pluripotent state. Experimental evidence suggests that individual iPSC lines may be "epigenetically unique" and predisposed to generate cells of a particular lineage. However, the authors believe that improvements to the culturing techniques may be able to overcome the variability and inefficiency described in this report.

These findings underpin the importance of understanding the inherent variability among discrete cell populations, whether they are iPSCs or ESCs. Characterizing the variability among iPSC lines will be crucial to apply the cells clinically. Indeed, the factors that make each iPSC line unique may also delay the cells' widespread use, as differences among the cell lines will affect comparisons and potentially influence their clinical behavior. For example, successfully modeling disease requires being able to identify the cellular differences between patients and controls that lead to dysfunction. These differences must be framed in the context of the biologic variability inherent in a given patient population. If iPSC lines are to be used to model disease or screen candidate drugs, then variability among lines must be minimized and characterized fully so that researchers can understand how their observed results match to the biology of the disease being studied. As such, standardized assays and methods will become increasingly important for the clinical application of iPSCs, and controls must be developed that account for variability among the iPSCs and their derivatives.

Additionally, researchers must understand the factors that initiate reprogramming towards pluripotency in different cell types. A recent report has identified one factor that initiates reprogramming in human fibroblasts,46 setting the groundwork for developing predictive models to identify those cells that will become iPSCs. An iPSC may carry a genetic "memory" of the cell type that it once was, and this "memory" will likely influence its ability to be reprogrammed. Understanding how this memory varies among different cell types and tissues will be necessary to reprogram successfully.

iPSCs have the potential to become multipurpose research and clinical tools to understand and model diseases, develop and screen candidate drugs, and deliver cell-replacement therapy to support regenerative medicine. This section will explore the possibilities and the challenges that accompany these medical applications, with the caveat that some uses are more immediate than others. For example, researchers currently use stem cells to test/screen drugs or as study material to identify molecules or genes implicated in regeneration. Conducting experiments or testing candidate drugs on human cells grown in culture enables researchers to understand fundamental principles and relationships that will ultimately inform the use of stem cells as a source of tissue for transplantation. Therefore, using iPSCs in cell-replacement therapies is a future application of these cells, albeit one that has tremendous clinical potential. The following discussion will highlight recent efforts toward this goal while recognizing the challenges that must be overcome for these cells to reach the clinic.

Reprogramming technology offers the potential to treat many diseases, including Alzheimer's disease, Parkinson's disease, cardiovascular disease, diabetes, and amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease). In theory, easily-accessible cell types (such as skin fibroblasts) could be biopsied from a patient and reprogrammed, effectively recapitulating the patient's disease in a culture dish. Such cells could then serve as the basis for autologous cell replacement therapy. Because the source cells originate within the patient, immune rejection of the differentiated derivatives would be minimized. As a result, the need for immunosuppressive drugs to accompany the cell transplant would be lessened and perhaps eliminated altogether. In addition, the reprogrammed cells could be directed to produce the cell types that are compromised or destroyed by the disease in question. A recent experiment has demonstrated the proof of principle in this regard,47 as iPSCs derived from a patient with ALS were directed to differentiate into motor neurons, which are the cells that are destroyed in the disease.

Although much additional basic research will be required before iPSCs can be applied in the clinic, these cells represent multi-purpose tools for medical research. Using the techniques described in this article, researchers are now generating myriad disease-specific iPSCs. For example, dermal fibroblasts and bone marrow-derived mesencyhmal cells have been used to establish iPSCs from patients with a variety of diseases, including ALS, adenosine deaminase deficiency-related severe combined immunodeficiency, Shwachman- Bodian-Diamond syndrome, Gaucher disease type III, Duchenne and Becker muscular dystrophies, Parkinson's disease, Huntington's disease, type 1 diabetes mellitus, Down syndrome/trisomy 21, and spinal muscular atrophy.4749 iPSCs created from patients diagnosed with a specific genetically-inherited disease can then be used to model disease pathology. For example, iPSCs created from skin fibroblasts taken from a child with spinal muscular atrophy were used to generate motor neurons that showed selective deficits compared to those derived from the child's unaffected mother.48 As iPSCs illuminate the development of normal and disease-specific pathologic tissues, it is expected that discoveries made using these cells will inform future drug development or other therapeutic interventions.

One particularly appealing aspect of iPSCs is that, in theory, they can be directed to differentiate into a specified lineage that will support treatment or tissue regeneration. Thus, somatic cells from a patient with cardiovascular disease could be used to generate iPSCs that could then be directed to give rise to functional adult cardiac muscle cells (cardiomyocytes) that replace diseased heart tissue, and so forth. Yet while iPSCs have great potential as sources of adult mature cells, much remains to be learned about the processes by which these cells differentiate. For example, iPSCs created from human50 and murine fibroblasts5153 can give rise to functional cardiomyocytes that display hallmark cardiac action potentials. However, the maturation process into cardiomyocytes is impaired when iPSCs are usedcardiac development of iPSCs is delayed compared to that seen with cardiomyocytes derived from ESCs or fetal tissue. Furthermore, variation exists in the expression of genetic markers in the iPSC-derived cardiac cells as compared to that seen in ESC-derived cardiomyocytes. Therefore, iPSC-derived cardiomyocytes demonstrate normal commitment but impaired maturation, and it is unclear whether observed defects are due to technical (e.g., incomplete reprogramming of iPSCs) or biological barriers (e.g., functional impairment due to genetic factors). Thus, before these cells can be used for therapy, it will be critical to distinguish between iPSC-specific and disease-specific phenotypes.

However, it must be noted that this emerging field is continually evolving; additional basic iPSC research will be required in parallel with the development of disease models. Although the reprogramming technology that creates iPSCs is currently imperfect, these cells will likely impact future therapy, and "imperfect" cells can illuminate many areas related to regenerative medicine. However, iPSC-derived cells that will be used for therapy will require extensive characterization relative to what is sufficient to support disease modeling studies. To this end, researchers have begun to use imaging techniques to observe cells that are undergoing reprogramming to distinguish true iPSCs from partially-reprogrammed cells.54 The potential for tumor formation must also be addressed fully before any iPSC derivatives can be considered for applied cell therapy. Furthermore, in proposed autologous therapy applications, somatic DNA mutations (e.g., non-inherited mutations that have accumulated during the person's lifetime) retained in the iPSCs and their derivatives could potentially impact downstream cellular function or promote tumor formation (an issue that may possibly be circumvented by creating iPSCs from a "youthful" cell source such as umbilical cord blood).55 Whether these issues will prove consequential when weighed against the cells' therapeutic potential remains to be determined. While the promise of iPSCs is great, the current levels of understanding of the cells' biology, variability, and utility must also increase greatly before iPSCs become standard tools for regenerative medicine.

Since their discovery four years ago, induced pluripotent stem cells have captured the imagination of researchers and clinicians seeking to develop patient-specific therapies. Reprogramming adult tissues to embryonic-like states has countless prospective applications to regenerative medicine, drug development, and basic research on stem cells and developmental processes. To this point, a PubMed search conducted in April 2010 using the term "induced pluripotent stem cells" (which was coined in 2006) returned more than 1400 publications, indicating a highly active and rapidlydeveloping research field.

However, many technical and basic science issues remain before the promise offered by iPSC technology can be realized fully. For putative regenerative medicine applications, patient safety is the foremost consideration. Standardized methods must be developed to characterize iPSCs and their derivatives. Furthermore, reprogramming has demonstrated a proof of-principle, yet the process is currently too inefficient for routine clinical application. Thus, unraveling the molecular mechanisms that govern reprogramming is a critical first step toward standardizing protocols. A grasp on the molecular underpinnings of the process will shed light on the differences between iPSCs and ESCs (and determine whether these differences are clinically significant). Moreover, as researchers delve more deeply into this field, the effects of donor cell populations can be compared to support a given application; i.e., do muscle-derived iPSCs produce more muscle than skin-derived cells? Based on the exciting developments in this area to date, induced pluripotent stem cells will likely support future therapeutic interventions, either directly or as research tools to establish novel models for degenerative disease that will inform drug development. While much remains to be learned in the field of iPSC research, the development of reprogramming techniques represents a breakthrough that will ultimately open many new avenues of research and therapy.

Chapter 9|Table of Contents|Chapter 11

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The Promise of Induced Pluripotent Stem Cells (iPSCs ...

This article is about imaging techniques and modalities for the human body. For imaging of animals in research, see Preclinical imaging.

Medical imaging is the technique and process of creating visual representations of the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to reveal internal structures hidden by the skin and bones, as well as to diagnose and treat disease. Medical imaging also establishes a database of normal anatomy and physiology to make it possible to identify abnormalities. Although imaging of removed organs and tissues can be performed for medical reasons, such procedures are usually considered part of pathology instead of medical imaging.

As a discipline and in its widest sense, it is part of biological imaging and incorporates radiology which uses the imaging technologies of X-ray radiography, magnetic resonance imaging, medical ultrasonography or ultrasound, endoscopy, elastography, tactile imaging, thermography, medical photography and nuclear medicine functional imaging techniques as positron emission tomography (PET) and Single-photon emission computed tomography (SPECT).

Measurement and recording techniques which are not primarily designed to produce images, such as electroencephalography (EEG), magnetoencephalography (MEG), electrocardiography (ECG), and others represent other technologies which produce data susceptible to representation as a parameter graph vs. time or maps which contain data about the measurement locations. In a limited comparison these technologies can be considered as forms of medical imaging in another discipline.

Up until 2010, 5billion medical imaging studies had been conducted worldwide.[1] Radiation exposure from medical imaging in 2006 made up about 50% of total ionizing radiation exposure in the United States.[2]

Medical imaging is often perceived to designate the set of techniques that noninvasively produce images of the internal aspect of the body. In this restricted sense, medical imaging can be seen as the solution of mathematical inverse problems. This means that cause (the properties of living tissue) is inferred from effect (the observed signal). In the case of medical ultrasonography, the probe consists of ultrasonic pressure waves and echoes that go inside the tissue to show the internal structure. In the case of projectional radiography, the probe uses X-ray radiation, which is absorbed at different rates by different tissue types such as bone, muscle and fat.

The term noninvasive is used to denote a procedure where no instrument is introduced into a patients body which is the case for most imaging techniques used.

In the clinical context, invisible light medical imaging is generally equated to radiology or clinical imaging and the medical practitioner responsible for interpreting (and sometimes acquiring) the images is a radiologist. Visible light medical imaging involves digital video or still pictures that can be seen without special equipment. Dermatology and wound care are two modalities that use visible light imagery. Diagnostic radiography designates the technical aspects of medical imaging and in particular the acquisition of medical images. The radiographer or radiologic technologist is usually responsible for acquiring medical images of diagnostic quality, although some radiological interventions are performed by radiologists.

As a field of scientific investigation, medical imaging constitutes a sub-discipline of biomedical engineering, medical physics or medicine depending on the context: Research and development in the area of instrumentation, image acquisition (e.g., radiography), modeling and quantification are usually the preserve of biomedical engineering, medical physics, and computer science; Research into the application and interpretation of medical images is usually the preserve of radiology and the medical sub-discipline relevant to medical condition or area of medical science (neuroscience, cardiology, psychiatry, psychology, etc.) under investigation. Many of the techniques developed for medical imaging also have scientific and industrial applications.[3]

Two forms of radiographic images are in use in medical imaging. Projection radiography and fluoroscopy, with the latter being useful for catheter guidance. These 2D techniques are still in wide use despite the advance of 3D tomography due to the low cost, high resolution, and depending on application, lower radiation dosages. This imaging modality utilizes a wide beam of x rays for image acquisition and is the first imaging technique available in modern medicine.

A magnetic resonance imaging instrument (MRI scanner), or nuclear magnetic resonance (NMR) imaging scanner as it was originally known, uses powerful magnets to polarize and excite hydrogen nuclei (i.e., single protons) of water molecules in human tissue, producing a detectable signal which is spatially encoded, resulting in images of the body.[4] The MRI machine emits a radio frequency (RF) pulse at the resonant frequency of the hydrogen atoms on water molecules. Radio frequency antennas (RF coils) send the pulse to the area of the body to be examined. The RF pulse is absorbed by protons, causing their direction with respect to the primary magnetic field to change. When the RF pulse is turned off, the protons relax back to alignment with the primary magnet and emit radio-waves in the process. This radio-frequency emission from the hydrogen-atoms on water is what is detected and reconstructed into an image. The resonant frequency of a spinning magnetic dipole (of which protons are one example) is called the Larmor frequency and is determined by the strength of the main magnetic field and the chemical environment of the nuclei of interest. MRI uses three electromagnetic fields: a very strong (typically 1.5 to 3 teslas) static magnetic field to polarize the hydrogen nuclei, called the primary field; gradient fields that can be modified to vary in space and time (on the order of 1kHz) for spatial encoding, often simply called gradients; and a spatially homogeneous radio-frequency (RF) field for manipulation of the hydrogen nuclei to produce measurable signals, collected through an RF antenna.

Like CT, MRI traditionally creates a two dimensional image of a thin slice of the body and is therefore considered a tomographic imaging technique. Modern MRI instruments are capable of producing images in the form of 3D blocks, which may be considered a generalization of the single-slice, tomographic, concept. Unlike CT, MRI does not involve the use of ionizing radiation and is therefore not associated with the same health hazards. For example, because MRI has only been in use since the early 1980s, there are no known long-term effects of exposure to strong static fields (this is the subject of some debate; see Safety in MRI) and therefore there is no limit to the number of scans to which an individual can be subjected, in contrast with X-ray and CT. However, there are well-identified health risks associated with tissue heating from exposure to the RF field and the presence of implanted devices in the body, such as pace makers. These risks are strictly controlled as part of the design of the instrument and the scanning protocols used.

Because CT and MRI are sensitive to different tissue properties, the appearance of the images obtained with the two techniques differ markedly. In CT, X-rays must be blocked by some form of dense tissue to create an image, so the image quality when looking at soft tissues will be poor. In MRI, while any nucleus with a net nuclear spin can be used, the proton of the hydrogen atom remains the most widely used, especially in the clinical setting, because it is so ubiquitous and returns a large signal. This nucleus, present in water molecules, allows the excellent soft-tissue contrast achievable with MRI.

A number of different pulse sequences can be used for specific MRI diagnostic imaging (multiparametric MRI or mpMRI). It is possible to differentiate tissue characteristics by combining two or more of the following imaging sequences, depending on the information being sought: T1-weighted (T1-MRI), T2-weighted (T2-MRI), diffusion weighted imaging (DWI-MRI), dynamic contrast enhancement (DCE-MRI), and spectroscopy (MRI-S). For example, imaging of prostate tumors is better accomplished using T2-MRI and DWI-MRI than T2-weighted imaging alone.[5] The number of applications of mpMRI for detecting disease in various organs continues to expand, including liver studies, breast tumors, pancreatic tumors, and assessing the effects of vascular disruption agents on cancer tumors.[6][7][8]

Nuclear medicine encompasses both diagnostic imaging and treatment of disease, and may also be referred to as molecular medicine or molecular imaging & therapeutics.[9] Nuclear medicine uses certain properties of isotopes and the energetic particles emitted from radioactive material to diagnose or treat various pathology. Different from the typical concept of anatomic radiology, nuclear medicine enables assessment of physiology. This function-based approach to medical evaluation has useful applications in most subspecialties, notably oncology, neurology, and cardiology. Gamma cameras and PET scanners are used in e.g. scintigraphy, SPECT and PET to detect regions of biologic activity that may be associated with disease. Relatively short lived isotope, such as 99mTc is administered to the patient. Isotopes are often preferentially absorbed by biologically active tissue in the body, and can be used to identify tumors or fracture points in bone. Images are acquired after collimated photons are detected by a crystal that gives off a light signal, which is in turn amplified and converted into count data.

Fiduciary markers are used in a wide range of medical imaging applications. Images of the same subject produced with two different imaging systems may be correlated (called image registration) by placing a fiduciary marker in the area imaged by both systems. In this case, a marker which is visible in the images produced by both imaging modalities must be used. By this method, functional information from SPECT or positron emission tomography can be related to anatomical information provided by magnetic resonance imaging (MRI).[12] Similarly, fiducial points established during MRI can be correlated with brain images generated by magnetoencephalography to localize the source of brain activity.

Medical ultrasonography uses high frequency broadband sound waves in the megahertz range that are reflected by tissue to varying degrees to produce (up to 3D) images. This is commonly associated with imaging the fetus in pregnant women. Uses of ultrasound are much broader, however. Other important uses include imaging the abdominal organs, heart, breast, muscles, tendons, arteries and veins. While it may provide less anatomical detail than techniques such as CT or MRI, it has several advantages which make it ideal in numerous situations, in particular that it studies the function of moving structures in real-time, emits no ionizing radiation, and contains speckle that can be used in elastography. Ultrasound is also used as a popular research tool for capturing raw data, that can be made available through an ultrasound research interface, for the purpose of tissue characterization and implementation of new image processing techniques. The concepts of ultrasound differ from other medical imaging modalities in the fact that it is operated by the transmission and receipt of sound waves. The high frequency sound waves are sent into the tissue and depending on the composition of the different tissues; the signal will be attenuated and returned at separate intervals. A path of reflected sound waves in a multilayered structure can be defined by an input acoustic impedance (ultrasound sound wave) and the Reflection and transmission coefficients of the relative structures.[11] It is very safe to use and does not appear to cause any adverse effects. It is also relatively inexpensive and quick to perform. Ultrasound scanners can be taken to critically ill patients in intensive care units, avoiding the danger caused while moving the patient to the radiology department. The real time moving image obtained can be used to guide drainage and biopsy procedures. Doppler capabilities on modern scanners allow the blood flow in arteries and veins to be assessed.

Elastography is a relatively new imaging modality that maps the elastic properties of soft tissue. This modality emerged in the last two decades. Elastography is useful in medical diagnoses, as elasticity can discern healthy from unhealthy tissue for specific organs/growths. For example, cancerous tumours will often be harder than the surrounding tissue, and diseased livers are stiffer than healthy ones.[13][14][15][16] There are a several elastographic techniques based on the use of ultrasound, magnetic resonance imaging and tactile imaging. The wide clinical use of ultrasound elastography is a result of the implementation of technology in clinical ultrasound machines. Main branches of ultrasound elastography include Quasistatic Elastography/Strain Imaging, Shear Wave Elasticity Imaging (SWEI), Acoustic Radiation Force Impulse imaging (ARFI), Supersonic Shear Imaging (SSI), and Transient Elastography.[14] In the last decade a steady increase of activities in the field of elastography is observed demonstrating successful application of the technology in various areas of medical diagnostics and treatment monitoring.

Tactile imaging is a medical imaging modality that translates the sense of touch into a digital image. The tactile image is a function of P(x,y,z), where P is the pressure on soft tissue surface under applied deformation and x,y,z are coordinates where pressure P was measured. Tactile imaging closely mimics manual palpation, since the probe of the device with a pressure sensor array mounted on its face acts similar to human fingers during clinical examination, slightly deforming soft tissue by the probe and detecting resulting changes in the pressure pattern. Figure on the right presents an experiment on a composite tissue phantom examined by a tactile imaging probe illustrating the ability of tactile imaging to visualize in 3D the structure of the object.

This modality is used for imaging of the prostate,[17] breast,[18]vagina and pelvic floor support structures,[19] and myofascial trigger points in muscle.[20]

Photoacoustic imaging is a recently developed hybrid biomedical imaging modality based on the photoacoustic effect. It combines the advantages of optical absorption contrast with ultrasonic spatial resolution for deep imaging in (optical) diffusive or quasi-diffusive regime. Recent studies have shown that photoacoustic imaging can be used in vivo for tumor angiogenesis monitoring, blood oxygenation mapping, functional brain imaging, and skin melanoma detection, etc.

Tomography is the imaging by sections or sectioning. The main such methods in medical imaging are:

When ultrasound is used to image the heart it is referred to as an echocardiogram. Echocardiography allows detailed structures of the heart, including chamber size, heart function, the valves of the heart, as well as the pericardium (the sac around the heart) to be seen. Echocardiography uses 2D, 3D, and Doppler imaging to create pictures of the heart and visualize the blood flowing through each of the four heart valves. Echocardiography is widely used in an array of patients ranging from those experiencing symptoms, such as shortness of breath or chest pain, to those undergoing cancer treatments. Transthoracic ultrasound has been proven to be safe for patients of all ages, from infants to the elderly, without risk of harmful side effects or radiation, differentiating it from other imaging modalities. Echocardiography is one of the most commonly used imaging modalities in the world due to its portability and use in a variety of applications. In emergency situations, echocardiography is quick, easily accessible, and able to be performed at the bedside, making it the modality of choice for many physicians.

FNIR Is a relatively new non-invasive imaging technique. NIRS (near infrared spectroscopy) is used for the purpose of functional neuroimaging and has been widely accepted as a brain imaging technique.[21]

Using superparamagnetic iron oxide nanoparticles, magnetic particle imaging (MPI) is a developing diagnostic imaging technique used for tracking superparamagnetic iron oxide nanoparticles. The primary advantage is the high sensitivity and specificity, along with the lack of signal decrease with tissue depth. MPI has been used in medical research to image cardiovascular performance, neuroperfusion, and cell tracking.

In response to increased concern by the public over radiation doses and the ongoing progress of best practices, The Alliance for Radiation Safety in Pediatric Imaging was formed within the Society for Pediatric Radiology. In concert with The American Society of Radiologic Technologists, The American College of Radiology and The American Association of Physicists in Medicine, the Society for Pediatric Radiology developed and launched the Image Gently Campaign which is designed to maintain high quality imaging studies while using the lowest doses and best radiation safety practices available on pediatric patients.[22] This initiative has been endorsed and applied by a growing list of various Professional Medical organizations around the world and has received support and assistance from companies that manufacture equipment used in Radiology.

Following upon the success of the Image Gently campaign, the American College of Radiology, the Radiological Society of North America, the American Association of Physicists in Medicine and the American Society of Radiologic Technologists have launched a similar campaign to address this issue in the adult population called Image Wisely.[23] The World Health Organization and International Atomic Energy Agency (IAEA) of the United Nations have also been working in this area and have ongoing projects designed to broaden best practices and lower patient radiation dose.[24][25][26]

Medical imaging may be indicated in pregnancy because of pregnancy complications, intercurrent diseases or routine prenatal care. Magnetic resonance imaging (MRI) without MRI contrast agents as well as obstetric ultrasonography are not associated with any risk for the mother or the fetus, and are the imaging techniques of choice for pregnant women.[27]Projectional radiography, X-ray computed tomography and nuclear medicine imaging result some degree of ionizing radiation exposure, but have with a few exceptions much lower absorbed doses than what are associated with fetal harm.[27] At higher dosages, effects can include miscarriage, birth defects and intellectual disability.[27]

The amount of data obtained in a single MR or CT scan is very extensive. Some of the data that radiologists discard could save patients time and money, while reducing their exposure to radiation and risk of complications from invasive procedures.[28] Another approach for making the procedures more efficient is based on utilizing additional constraints, e.g., in some medical imaging modalities one can improve the efficiency of the data acquisition by taking into account the fact the reconstructed density is positive.[29]

Volume rendering techniques have been developed to enable CT, MRI and ultrasound scanning software to produce 3D images for the physician.[30] Traditionally CT and MRI scans produced 2D static output on film. To produce 3D images, many scans are made, then combined by computers to produce a 3D model, which can then be manipulated by the physician. 3D ultrasounds are produced using a somewhat similar technique. In diagnosing disease of the viscera of abdomen, ultrasound is particularly sensitive on imaging of biliary tract, urinary tract and female reproductive organs (ovary, fallopian tubes). As for example, diagnosis of gall stone by dilatation of common bile duct and stone in common bile duct. With the ability to visualize important structures in great detail, 3D visualization methods are a valuable resource for the diagnosis and surgical treatment of many pathologies. It was a key resource for the famous, but ultimately unsuccessful attempt by Singaporean surgeons to separate Iranian twins Ladan and Laleh Bijani in 2003. The 3D equipment was used previously for similar operations with great success.

Other proposed or developed techniques include:

Some of these techniques[examples needed] are still at a research stage and not yet used in clinical routines.

Neuroimaging has also been used in experimental circumstances to allow people (especially disabled persons) to control outside devices, acting as a brain computer interface.

Many medical imaging software applications (3DSlicer, ImageJ, MIPAV, ImageVis3D, etc.) are used for non-diagnostic imaging, specifically because they dont have an FDA approval[31] and not allowed to use in clinical research for patient diagnosis.[32] Note that many clinical research studies are not designed for patient diagnosis anyway.[33]

Used primarily in ultrasound imaging, capturing the image produced by a medical imaging device is required for archiving and telemedicine applications. In most scenarios, a frame grabber is used in order to capture the video signal from the medical device and relay it to a computer for further processing and operations.[34]

The Digital Imaging and Communication in Medicine (DICOM) Standard is used globally to store, exchange, and transmit medical images. The DICOM Standard incorporates protocols for imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography, and radiation therapy.[35] DICOM includes standards for image exchange (e.g., via portable media such as DVDs), image compression, 3-D visualization, image presentation, and results reporting.[36]

Medical imaging techniques produce very large amounts of data, especially from CT, MRI and PET modalities. As a result, storage and communications of electronic image data are prohibitive without the use of compression. JPEG 2000 is the state-of-the-art image compression DICOM standard for storage and transmission of medical images. The cost and feasibility of accessing large image data sets over low or various bandwidths are further addressed by use of another DICOM standard, called JPIP, to enable efficient streaming of the JPEG 2000 compressed image data.

There has been growing trend to migrate from PACS to a Cloud Based RIS. A recent article by Applied Radiology said, As the digital-imaging realm is embraced across the healthcare enterprise, the swift transition from terabytes to petabytes of data has put radiology on the brink of information overload. Cloud computing offers the imaging department of the future the tools to manage data much more intelligently.[37]

Medical imaging has become a major tool in clinical trials since it enables rapid diagnosis with visualization and quantitative assessment.

A typical clinical trial goes through multiple phases and can take up to eight years. Clinical endpoints or outcomes are used to determine whether the therapy is safe and effective. Once a patient reaches the endpoint, he or she is generally excluded from further experimental interaction. Trials that rely solely on clinical endpoints are very costly as they have long durations and tend to need large numbers of patients.

In contrast to clinical endpoints, surrogate endpoints have been shown to cut down the time required to confirm whether a drug has clinical benefits. Imaging biomarkers (a characteristic that is objectively measured by an imaging technique, which is used as an indicator of pharmacological response to a therapy) and surrogate endpoints have shown to facilitate the use of small group sizes, obtaining quick results with good statistical power.[38]

Imaging is able to reveal subtle change that is indicative of the progression of therapy that may be missed out by more subjective, traditional approaches. Statistical bias is reduced as the findings are evaluated without any direct patient contact.

Imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are routinely used in oncology and neuroscience areas,.[39][40][41][42] For example, measurement of tumour shrinkage is a commonly used surrogate endpoint in solid tumour response evaluation. This allows for faster and more objective assessment of the effects of anticancer drugs. In Alzheimers disease, MRI scans of the entire brain can accurately assess the rate of hippocampal atrophy, while PET scans can measure the brains metabolic activity by measuring regional glucose metabolism,[38] and beta-amyloid plaques using tracers such as Pittsburgh compound B (PiB). Historically less use has been made of quantitative medical imaging in other areas of drug development although interest is growing.[43]

An imaging-based trial will usually be made up of three components:

Lead is the main material used for radiographic shielding against scattered X-rays.

In magnetic resonance imaging, there is MRI RF shielding as well as magnetic shielding to prevent external disturbance of image quality.

Read this article:Medical imaging Wikipedia

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Medical imaging Wikipedia IPS Cell Therapy IPS Cell ...

iPSCells Represent a Superior Approach

iPS cell-derived cardiomyocyte patch demonstrates spontaneous and synchronized contractions after 4 days in culture.

One of the greatest promises of human stem cells is to transform these early-stage cells into treatments for devastating diseases. Stem cells can potentially be used to repair damaged human tissues and to bioengineer transplantable human organs using various technologies, such as 3D printing. Using stem cells derived from another person (allogeneic transplantation) or from the patient (autologous transplantation), research efforts are underway to develop new therapies for historically difficult to treat conditions. In the past, adult stem and progenitor cells were used, but the differentiation of these cell types has proven to be difficult to control. Initial clinical trials using induced pluripotent stem (iPS) cells indicate that they are far superior for cellular therapy applications because they are better suited to scientific manipulation.

CDIs iPS cell-derived iCell and MyCell products are integral to the development of a range ofcell therapyapplications. A study using iCell Cardiomyocytesas part of a cardiac patch designed to treat heart failure is now underway. This tissue-engineered implantable patch mayemerge as apotential myocardial regeneration treatment.

Another study done with iPS cell-derived cells and kidney structures has marked an important first step towards regenerating, and eventually transplanting, a functioning human organ. In this work, iCell Endothelial Cellswere used to help to recapitulatethe blood supply of a laboratory-generated kidney scaffold. This type of outcome will be crucial for circulation and nutrient distribution in any rebuilt organ.

iCell Endothelial Cells revascularize kidney tissue. (Data courtesy of Dr. Jason Wertheim, Northwestern University)

CDI and its partners are leveraging iPS cell-derived human retinal pigment epithelial (RPE) cells to develop and manufacture autologous treatments for dry age-related macular degeneration (AMD). The mature RPE cells will be derivedfrom the patients own blood cells using CDIs MyCell process. Ifapproved by the FDA, this autologous cellular therapy wouldbe one of the first of its kind in the U.S.

Learn more about the technologybehind the development of these iPScell-derived cellular therapies.

Read more here:
Cellular Therapy - The World Leader in Stem Cell Technology

This weeks roundup of recent developments in neuroscience kicks off with a study from MIT, where engineers have devised a way to automate the process of monitoring neurons in a living brain using a computer algorithm that analyzes microscope images and guides a robotic arm to the target cell. In the above image, a pipette guided by a robotic arm approaches a neuron identified with a fluorescent stain.

Neurosurgeons at the Center for iPS Cell Research and Application, Kyoto University. They report two new ways to improve outcomes of induced pluropontent stem cell-based therapies for Parkinsons disease in monkey brains. The findings are a key step for patient recruitment of the first iPS cell-based therapy to treat neurodegenerative diseases, since one of the last steps before treating patients with an experimental cell therapy for the brain is confirmation that the therapy works in monkeys.

In other Parkinsons news, the FDA has denied Acorda Therapeutics New Drug Application filing for Inbrija. Inbrija is an inhaled, self-administered, form of levodopa for treating Parkinsons disease. According to the FDA, reason for the denial were the date when the manufacturing site would be ready for inspection, and a question regarding submission of the drug master production record. FDA also requested additional information at resubmission, which was not part of the basis for the refusal.

At the University of Turku, in Finland, researchers have revealed how eating stimulates the brains endogenous opioid system to signal pleasure and satiety. Interestingly, eating both bland and delicious meals triggered significant opioid release in the brain.

A young New York woman with severe headaches represented a never-before-seen case for neurosurgeons at New York Presbyterian. She was diagnosed with an unusual form of hydrocephalus/Chiari malformation, in which the skull is too small and restricted the brain. More about her in the video below:

Tinnitus, a chronic ringing or buzzing in the ears, has eluded medical treatment and scientific understanding. A new University of Illinois at Urbana-Champaign study found that chronic tinnitus is associated with changes in certain networks in the brain, and furthermore, those changes cause the brain to stay more at attention and less at rest. The finding provides patients with validation of their experiences and hope for future treatment options.

In social media news, research by BuzzFeed found more than half of the most-shared scientific stories about autism published in the last five years promote unevidenced or disproven treatments, or purported causes. More disturbingly, families in the autism community are excessively targeted by purveyors of bad information, making them more vulnerable to harmful, unproven so-called treatments.

Top Image: Ho-Jun Suk

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This Week In Neuroscience News 8/31/17 - ReliaWire

Stem cells and genome editing offer exciting opportunities within regenerative medicine.

However, any clinical application of stem cells requires strict regulation to ensure that the cells are not exposed to animal derived products.

Now Amsbio announces the availability of StemFit Basic02 feeder-free stem cell culture media.

StemFit Basic02 is a xeno-free, defined medium for human pluripotent stem cell (hiPSC) culture that offers an effective solution for regenerative medicine research.

This medium has been proven to effectively maintain Induced Pluripotent Stem (iPS) and Embryonic Stem (ES) cells under feeder-free conditions, during the reprogramming, expansion and differentiation phases of stem cell culture.

Specially formulated to enhance single cell expansion in the cloning step of stem cell genome editing, StemFit Basic02 offers superior and stable growth performance, high colony forming efficiency and robust scalable cell expansion.

This ensures high karyotype stability over long periods and hence reproducible culture conditions.

StemFit cell culture media has been independently evaluated by CGT Catapult, an independent centre of excellence helping advance the UK cell and gene therapy industry.

In these tests, StemFit not only delivered higher cell proliferation, but also showed characteristics such as homogeneity of gene expression compared with iPS cells cultured with four other media without any chromosomal abnormalities.

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Xeno-free cell culture medium for regenerative medicine research - Scientist Live

Stem cells and genome editing offer exciting opportunities within regenerative medicine. However, any clinical application of stem cells requires strict regulation to ensure that the cells are not exposed to animal derived products.

StemFit Basic02 is a xeno-free, defined medium for human pluripotent stem cell (hiPSC) culture that offers an effective solution for regenerative medicine research. This medium has been proven to effectively maintain Induced Pluripotent Stem (iPS) and Embryonic Stem (ES) cells under feeder-free conditions, during the reprogramming, expansion and differentiation phases of stem cell culture.

Specially formulated to enhance single cell expansion in the cloning step of stem cell genome editing, StemFit Basic02 offers superior and stable growth performance, high colony forming efficiency and robust scalable cell expansion. This ensures high karyotype stability over long periods and hence reproducible culture conditions.

StemFit cell culture media has been independently evaluated by CGT Catapult, an independent centre of excellence helping advance the UK cell and gene therapy industry. In these tests, StemFit not only delivered higher cell proliferation, but also showed characteristics such as homogeneity of gene expression compared with iPS cells cultured with 4 other media without any chromosomal abnormalities.

More:
Xeno-free Cell Culture Medium for Regenerative Medicine Research - Technology Networks

Monkeys show reduced Parkinsonian symptoms following a donor-matched iPS cell-based therapy. Misaki Ouchida, Center for iPS Cell Research and Application, Kyoto University

One of the last steps before treating patients with an experimental cell therapy for the brain is confirmation that the therapy works in monkeys. In its latest study, the Jun Takahashi lab shows monkeys with Parkinson's disease symptoms show significant improvement over two years after being transplanted neurons prepared from human iPS cells. The study, which can be read in Nature, is expected to be a final step before the first iPS cell-based therapy for a neurodegenerative disease.

Parkinson's disease degenerates a specific type of cells in the brain known as dopaminergic (DA) neurons. It has been reported that when symptoms are first detected, a patient will have already lost more than half of his or her DA neurons. Several studies have shown the transplantation of DA neurons made from fetal cells can mitigate the disease. The use of fetal tissues is controversial, however. On the other hand, iPS cells can be made from blood or skin, which is why Professor Takahashi, who is also a neurosurgeon specializing in Parkinson's disease, plans to use DA neurons made from iPS cells to treat patients.

"Our research has shown that DA neurons made from iPS cells are just as good as DA neurons made from fetal midbrain. Because iPS cells are easy to obtain, we can standardize them to only use the best iPS cells for therapy, " he said.

To test the safety and effectiveness of DA neurons made from human iPS cells, Tetsuhiro Kikuchi, a neurosurgeon working in the Takahashi lab, transplanted the cells into the brains of monkeys.

"We made DA neurons from different iPS cells lines. Some were made with iPS cells from healthy donors. Others were made from Parkinson's disease patients," said Kikuchi, who added that the differentiation method used to convert iPS cells into neurons is suitable for clinical trials.

It is generally assumed that the outcome of a cell therapy will depend on the number of transplanted cells that survived, but Kikuchi found this was not the case. More important than the number of cells was the quality of the cells.

"Each animal received cells prepared from a different iPS cell donor. We found the quality of donor cells had a large effect on the DA neuron survival," Kikuchi said.

To understand why, he looked for genes that showed different expression levels, finding 11 genes that could mark the quality of the progenitors. One of those genes was Dlk1.

"Dlk1 is one of the predictive markers of cell quality for DA neurons made from embryonic stem cells and transplanted into rat. We found Dlk1 in DA neurons transplanted into monkey. We are investigating Dlk1 to evaluate the quality of the cells for clinical applications."

Another feature of the study that is expected to extend to clinical study is the method used to evaluate cell survival in the host brains. The study demonstrated that magnetic resonance imaging (MRI) and position electron tomography (PET) are options for evaluating the patient post surgery.

"MRI and PET are non-invasive imaging modalities. Following cell transplantation, we must regularly observe the patient. A non-invasive method is preferred," said Takahashi.

The group is hopeful that it can begin recruiting patients for this iPS cell-based therapy before the end of next year. "This study is our answer to bring iPS cells to clinical settings," said Takahashi.

This article has been republished frommaterialsprovided byCIRA, Kyoto University. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Monkeys With Parkinson's Disease Successfully Treated With Human Stem Cell Transplants - Technology Networks

B. Bick, . Poindexter, UT Med. School/SPL

A depletion of brain cells that produce dopamine is responsible for the mobility problems seen in people with Parkinsons disease.

Japanese researchers report promising results from an experimental therapy for Parkinsons disease that involves implanting neurons made from reprogrammed stem cells into the brain. A trial conducted in monkeys with a version of the disease showed that the treatment improved their symptoms and seemed to be safe, according to a report published on 30 August in Nature1.

The studys key finding that the implanted cells survived in the brain for at least two years without causing any dangerous effects in the body provides a major boost to researchers hopes of testing stem-cell treatments for Parkinsons in humans, say scientists.

Jun Takahashi, a stem-cell scientist at Kyoto University in Japan who led the study, says that his team plans to begin transplanting neurons made from induced pluripotent stem (iPS) cells into people with Parkinsons in clinical trials soon.

The research is also likely to inform several other groups worldwide that are testing different approaches to treating Parkinsons using stem cells, with trials also slated to begin soon.

Nature breaks down the latest research and what it means for the future of stem-cell treatments.

Parkinsons is a neurodegenerative condition caused by the death of cells called dopaminergic neurons, which make a neurotransmitter called dopamine in certain areas of the brain. Because dopamine-producing brain cells are involved in movement, people with the condition experience characteristic tremors and stiff muscles. Current treatments address symptoms of the disease but not the underlying cause.

Researchers have pursued the idea that pluripotent stem cells, which can form any cell type in the body, could replace dead dopamine-making neurons in people with Parkinsons, and thus potentially halt or even reverse disease progression. Embryonic stem cells, derived from human embryos, have this capacity, but they have been the subject of ethical debates. Induced pluripotent stem (iPS) cells, which are made by coaxing adult cells into an emybronic-like state, have the same versatility without the associated ethical concerns.

Takahashis team transformed iPS cells derived from both healthy people and those with Parkinsons into dopamine-producing neurons. They then transplanted these cells into macaque monkeys with a form of the disease induced by a neuron-killing toxin.

The transplanted brain cells survived for at least two years and formed connections with the monkeys brain cells, potentially explaining why the monkeys treated with cells began moving around their cages more frequently.

Crucially, Takahashis team found no sign that the transplanted cells had developed into tumours a key concern with treatments that involve pluripotent cells or that they evoked an immune response that couldnt be controlled with immune-suppressing drugs.

Its addressing a set of critical issues that need to be investigated before one can, with confidence, move to using the cells in humans, says Anders Bjorklund, a neuroscientist at Lund University in Sweden.

I hope we can begin a clinical trial by the end of next year, says Takahashi. Such a trial would be the first iPS cell trial for Parkinson's. In 2014, a Japanese woman in her 70s became the first person to receive cells derived from iPS cells, to treat her macular degeneration.

In theory, iPS cells could be tailor-made for individual patients, which would eliminate the need to use drugs that suppress a possible immune response to foreign tissues.

But customized iPS cells are expensive to make and can take a couple months to derive and grow, Takahashi notes. So his team instead plans to establish iPS cell lines from healthy people and then use immune cell biomarkers to match them to people with Parkinsons in the hope of minimizing the immune response (and therefore the need for drugs to blunt the attack).

In a study described in an accompanying paper in Nature Communications2, Takahashis team implanted into monkeys iPS-cell-derived neurons from different macaques. They found that transplants between monkeys carrying similar white blood cell markers triggered a muted immune reaction.

Earlier this year, Chinese researchers began a Parkinsons trial that used a different approach: giving patients neural-precursor cells made from embryonic stem cells, which are intended to develop into mature dopamine-producing neurons. A year earlier, in a separate trial, patients in Australia received similar cells. But some researchers have expressed concerns that the immature transplanted cells could develop tumour-causing mutations.

Meanwhile, researchers who are part of a Parkinsons stem-cell therapy consortium called GForce-PD, of which Takahashis team is a member, are set to bring still other approaches to the clinic. Teams in the United States, Sweden and the United Kingdom are all planning trials to transplant dopamine-producing neurons made from embryonic stem cells into humans. Previously established lines of embryonic stem cells have the benefit that they are well studied and can be grown in large quantities, and so all trial participants can receive a standardized treatment, notes Bjorklund, also a consortium member.

Jeanne Loring, a stem-cell scientist at the Scripps Research Institute in La Jolla, California, favours transplanting iPS-derived neurons made from a patients own cells. Although expensive, this approach avoids dangerous immunosuppressive drugs, she says. And because iPS cells are established anew for each patient, the lines go through relatively few cell divisions, minimizing the risk that they will develop tumour-causing mutations. Loring hopes to begin her teams trial in 2019. This shouldnt be a race and were cheering for success by all, she says.

Lorenz Studer, a stem-cell scientist at the Memorial Sloan Kettering Cancer Center in New York City who is working on a trial that will use neurons made from embryonic stem cells, says that there are still issues to work out, such as the number of cells needed in each transplant procedure. But he says that the latest study is a sign that we are ready to move forward.

See original here:
Reprogrammed cells relieve Parkinson's symptoms in trials - Nature.com

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Mitalipov successfully repairs genes in human embryos

A ground breaking discovery by Shoukhrat Mitalipov, Ph.D.,was reported in Nature the successful removal of a lethal geneticdefect in human embryos. The breakthrough is the initial confirmation that adangerous genetic defect can in theory be erased.

Scientific success in embryo editing re-opens reg debate. BioWorld

Study in Nature demonstrates method for repairing genes in human embryos that prevents inherited diseases. OHSU News

Gene Editing Breakthrough. Charlie Rose Show

A Promising And Still Uncertain Future For Human Gene Editing. Science Friday

In Breakthrough, Scientists Edit a Dangerous Mutation From Genes in Human Embryos. NY Times

First human embryo editing experiment in U.S.'corrects' gene for heart condition. The Washington Post.

Scientists Precisely Edit DNA In Human Embryos To Fix A Disease Gene. NPR

Human embryos edited to stop disease. BBC

A Gene Editing Breakthrough. On Point with Tom Ashbrook.

First U.S.-based group to edit human embryos brings practice closer to clinic. Science

In breakthrough, OHSU corrects defective gene in embryo. Oregonlive.

First Safe Repair of Gene in Human Embryos. Associated Press.

A new discovery may unlock the answer to a vexing scientificquestion: How to conduct mitochondrial replacement therapy, a new gene-therapytechnique, in such a way that safely prevents the transmission of harmful mitochondrialgene mutations from mothers to their children.

For women with mitochondrial diseases, a step closer to preventing transmission. STAT

Human embryo experiment shows progress toward 'three-parent' babies. The Washington Post

Families struggling with infertility or a genetic predisposition for debilitating mitochondrial diseases may someday benefit from a new breakthrough led by scientists at OHSU and the Salk Institute for Biological Studies.

Egg 'nobbles' can be used to create embryos, say scientists in fertility breakthrough

Fertility success may get boost from new research

First he pioneered a new way of making life. Now he wants to try it in people

Shoukhrat Mitalipov: The cloning chief.

Researchers announced they had derived stem cells fromcloned human embryos, a long-awaited research coup that Science's editors choseas a runner-up for Breakthrough of the Year.Read the article on Science

#4. Finally, We're Just Like Dolly

#5. Functioning Organs Made From Stem Cells

#2. Human embryonic stem cells cloned

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Center for Embryonic Cell and Gene Therapy | Center for ...

Social security expenditures keep rising endlessly as the aging of Japans population accelerates with the low birthrate. Yet, little is known about the way huge sums of taxpayer money are being poured into wasteful projects tied to vested interests in the name of saving human lives.

The Japan Agency for Medical Research and Development (AMED), which Prime Minister Shinzo Abe created with much fanfare in 2015 as a counterpart to the U.S. National Institute of Health, has an annual budget in excess of 140 billion. But the National Cancer Center (NCC), which is supposed to be a major recipient of the AMED fund, is in trouble because excessive sums have been spent on construction of buildings and facilities in the name of life science research.

A glance at the NCCs financial statements shows that its retained earnings plummeted from 5.6 billion in fiscal 2010 to 762 million in 2015. The steep fall in the retained earnings is not due to cuts in grants from the Health, Labor and Welfare Ministry, as a high-ranking NCC official claims. The NCC earned 31.4 billion from medical services and 4.3 billion from research projects in fiscal 2010, and these earnings rose by 41 percent to 44.4 billion and 14 percent to 9.2 billion, respectively, unequivocally showing that the rise in earnings far exceeded the cut in government grants.

Then why have its retained earnings fallen so rapidly? The answer is that excessive investments in construction of new facilities have eaten into its funds. For example, it cost 5.4 billion to build a new research center on next-generation surgery and endoscopy, which was completed in May, and another 16.7 billion to build a new research laboratory that began operating in July. The question here is not the sheer sum spent on these projects, but their balance with the institutes earnings. During the 2010-16 period, money spent on such construction projects exceeded the NCCs operating income by 44.3 billion. It seems clear that the NCC is investing beyond its means even as construction costs surge ahead of the 2020 Tokyo Olympic Games.

Cases of advanced medicine becoming an arena for big spending like public works projects are also found in the field of heavy particle therapy. Japan has five institutions specializing in this field, the pioneer among them being the National Institute of Radiological Sciences in Chiba Prefecture. The number in Japan represents nearly half of the 11 such facilities now operating worldwide.

The five heavy particle therapy facilities are located in Chiba, Hyogo, Gunma, Saga and Kanagawa prefectures, with one more being planned in Yamagata. And oddly enough, though, the NCC supposedly the control tower of cancer therapy in Japan has no such institute. That is said to be because those institutes were located in facilities with close links to the Education, Culture, Sports, Science and Technology Ministry which took the lead in the development of heavy particle therapy instead of the health ministry.

One reason why Gunma University has one of those institutes is not because the university excelled in cancer treatment but, according to a source familiar with the decision, because of the influence of former education minister Hirofumi Nakasone, an Upper House member elected from the Gunma constituency and a powerful member of the Liberal Democratic Partys education lobby. Gunma Prefecture was eager to have the facility established there because that involved heavy initial investments about 7 billion each for the buildings and radiation equipment providing huge economic benefits to local construction and other related industries.

Haphazard ways in which money is being spent on advanced medical research are also found in the projects for biobanks, institutions that collect and preserve biospecimens of people such as blood, urine and DNA samples. Through followup research on the registered people and linking with their clinical information, their activities are expected to contribute to identifying the causes of illnesses and developing new medicines.

Of a number of biobanks set up in Japan, the Tohoku Medical Megabank Organization at Tohoku University is by far the largest. It started operating in fiscal 2011 as part of a series of government projects for recontruction from the Great East Japan Earthquake and tsunami that hit the regions Pacific coast. In its initial year of operation, more than 10 billion from the government budget was poured into the Tohoku Medical Megabank. A total of 5.1 billion was spent on the construction and design of a seven-story complex and another 7.5 billion on its facilities and equipment in the years through fiscal 2013. While spending was scaled back in subsequent years, 4.5 billion has been set aside for the project in fiscal 2017 a sum equivalent to the funding allocated to Kyoto University for its research on iPS (induced pluripotent stem) cells.

Tohoku Medical Megabank is staffed with 32 professors, 10 associate professors and 25 instructors. However, some of the staff are deemed not necessarily fit for the types of work assigned to the institute, leading some students to comment sarcastically that those who have failed to be promoted to full professorship at Tohoku University have been given new jobs at the biobank. Moreover, the quality of some of the work performed by the institute has been called into question.

The value of biobank is determined by the quality of the data obtained by its research. If the quality is poor, such an institute would not be trusted by researchers in pharmaceutical companies or other institutes. Six years after its creation, Tohoku Medical Megabanks achievement remains poor in terms of significant research that would have lured pharmaceutical firms and others to collaborate with the institute. The head of the biobank is not deterred, however, as he says his institutes research projects take time before tangible results can be produced, and the institute keeps asking for more funding from the AMED.

As funding for Tohoku Medical Megabank gets prioritized, budgetary allocations for the more prestigious BioBank Japan, which has been jointly established by the government-affiliated Riken research institute and the University of Tokyos Institute of Medical Science, has been significantly reduced. The budget cut by AMED is about to deal a fatal blow to the institute that has played a leading role in genome research in Japan.

Given Japans dire fiscal conditions, government funding on scientific research cannot be an exception to budget cuts. Time will come sooner or later for the generous funding for Tohoku Medical Megabank to be curtailed. Today, however, huge sums of taxpayer money are being poured on the institute despite its poor records of significant achievements in the name of the reconstruction of the areas ravaged by the 2011 disasters. Along with the spending of taxpayer money, new positions are being created for post-retirement jobs for government bureaucrats.

The circumstances surrounding those advanced medical research institutes look similar to those involving the governments public works projects: Securing funding from taxpayer money becomes more important than the outcome of projects. Unless the structure is fixed, there will be no hope of medical science becoming a core of the governments growth strategy.

This is an abridged translation of an article from the August issue of Sentaku, a monthly magazine covering political, social and economic scenes. More English articles can be read at http://www.sentaku-en.com

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Wasteful spending on medical public works - The Japan Times

Theres a lot to be said for being in the right place at the right time, but could Air Supplys long-time success be the result or a chance meeting or was the cosmos working overtime on a little something called destiny? Maybe, but one thing is for surenone of it would have been possible at all without their hard work and tenacity to make it happen.The two Russells, Graham Russell and Russell Hitchcock, happened to be cast in the same Sydney, Australian production of Jesus Christ Superstar in 1975, and everything changed after that.

Many an audience member has probably asked himself if a fine looking group of ladies about to take the stage could possibly do justice to one of the most popular rock bands in the world. Its a legitimate question considering its not easy music to play, so a person cant help but wonder if the music will be taken as seriously as the people in the audience do. However, once the guitars are plugged in and the girls dig into those first few chords, the obvious answer to that question is, oh, hell, yes.

Many a cook tries their hand at duplicating foods they love in restaurants and specialty shops, telling themselves, it cant be that difficult. Often times, theyre right. It can be doneand its pretty simple. However, sometimes, its not as easy as it looks.Mexican food for example looks easy because ingredients are simple, sauces are often slow-cooked and meat is marinated, making this comfort food one of Americas favorite. Recipes are often handed down and each time theyre prepared, a spice might be tweaked or flavor added, depending on taste and preference.

Its been 40 years since Elvis Presley died (August 16, 1977) and millions of people still have the date circled in red on their calendars. People still remember and they still mourn. Some internet sites have gone to the extent of estimating what he would look like now, if he were still here in the physical.This time of year Memphis fills up with more people than usual as crowds in large numbers make their pilgrimages to Graceland for visits to his home while tribute shows pop up all around the country to remember the huge icon that he was.

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For Immune System Stem Cell Studies, Mice Aren't Enough Science 2.0 Stem cell therapy is all the rage, with suspect companies sprouting up like supplement stores, claiming to be a benefit for this and that. Often all they have are mouse studies and FDA disclaimers on ... The authors found that two varieties of ... and more »

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For Immune System Stem Cell Studies, Mice Aren't Enough - Science 2.0

Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics

Over the past few years, the regulatory landscape for cell therapy development has grown increasingly complex. There are now accelerated pathways for advanced therapy medicinal products (ATMPs) in several countries worldwide, including the U.S., Japan, and South Korea. While the possibility for accelerated commercialization has resulted from these changes, substantial complexity has also been introduced, making it a more elaborate process to move cell therapy products from bench to bedside.

In the interview with Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics, we get an experts perspective on how the regulatory environment has changed and new opportunities that exist for bringing cell therapy products through the clinical trial process and into the global marketplace.

Yaron Ramati: I have 10 years of experience in regulatory affairs in biotechnology companies in Israel.

I have a PhD in Philosophy of Biology from the London School of Economics and an M.Sc. from the Technion in Neurobiology

Yaron Ramati:The United States, Japan, and South Korea are countries that have accelerated pathways that are unique for cell and gene therapies. Legislation took effect in Japan in late 2014, in South Korea in 2016, and in the United States in 2017.

Additionally, the EU has a program for product acceleration the Adaptive Pathways. Although it is not explicitly for cell and gene therapies, these have been given a lot of attention by the group.

Yaron Ramati:

In the United States: Regenerative medicine advanced therapy (RMAT) designation.Cell therapies that aim to treat serious medical conditions with high unmet need, and have preliminary favorable clinical data, can get the designation. It allows for accelerated approval (i.e., the use of biomarkers and intermediate endpoints for BLA, priority review).

In Japan: Conditional time-limited marketing authorization.This program allows for regenerative therapies (cell, gene and tissue therapies) to receive conditional marketing authorization for up to 7 years, following confirmation of safety and an initial proof of efficacy in Japan in diseases that are serious and have a high unmet need.

In South Korea: Conditional marketing authorization for cell therapy.As in Japan, this program allows for cell therapies to receive conditional marketing authorization for a limited time, following an initial proof of efficacy in serious diseases.

In EU: Adaptive Pathways pilot program. This program is a pilot program established by the EMA to explore ways in which the EMA can assist the streamlining the development of new promising therapies for serious conditions with high unmet need. Although this program is not explicitly for cell or gene therapy, it is the main focus of the group.

Yaron Ramati: All EU countries have a joint definition for ATMPs as set by EU regulation. Other countries have separate definitions that only partially overlap.

Yaron Ramati: Only few countries in the world are willing to be the first to provide marketing authorization for novel therapies. For ATMPs, European regulation does not allow individual countries in the union to provide marketing authorization, and so the EMA is the only gateway for ATMPs in Europe.

The U.S. FDA, Japan PMDA, and South Korea KFDA are the only others that are willing to be first to approve ATMPs.

Yaron Ramati: Currently, the EMA and PMDA are leading with four marketing approvals of cell and gene therapies each. RMAT designation procedure in the U.S. is expecting to give a boost to the products that are being developed for the U.S. market.

Yaron Ramati: Pluristem is very active in the field of accelerated development of its products. PLX-PAD of Pluristem has been accepted to the Japan conditional time-limited marketing authorization scheme by PMD, as well as to the adaptive pathways program of the EMA. It is active in both programs.

In addition, Pluristem intends to make use of the accelerated pathways offered for regenerative therapies in both the U.S. and in South Korea.

Yaron Ramati: The focus of Pluristem in these programs is the advancement of PLX-PAD. Pluristem had achieved understandings with EMA and PMDA regarding the accelerated approval of PLX-PAD for the treatment of critical limb ischemia (CLI).

It is the intention of Pluristem to achieve similar understandings with FDA, EMA, PMDA and KFDA regarding the development of PLX-PAD for the treatment of patients following hip fractures.

Yaron Ramati: PLX-PAD was accepted into the EMA adaptive pathways pilot program in 2015. Since then, Pluristem has taken advantage of this program in coming to an understanding with the EMA on the desired regulatory path of PLX-PAD in CLI. In addition, Pluristem undertook parallel scientific advice with the EMA and leading health technology assessment (HTA) bodies in Europe.

In this meeting, Pluristem received valuable feedback on the expectations that these bodies have for purposes of reimbursement in Europe. Pluristem has designed the Phase 3 PACE study in CLI patients in view of the feedback received from both the EMA and the HTA bodies, with the purpose of addressing their respective expectations.

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An Experts Perspective on Accelerated Pathways for Cell ...

Stem cell science involves many technical terms. This glossary covers many of the common terms you will encounter in reading about stem cells.

Adult stem cellsA commonly used term for tissue-specific stem cells, cells that can give rise to the specialized cells in specific tissues. Includes all stem cells other than pluripotent stem cells such as embryonic and induced pluripotent stem cells.

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AutologousCells or tissues from the same individual; an autologous bone marrow transplant involves one individual as both donor and recipient.

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Basic researchResearch designed to increase knowledge and understanding (as opposed to research designed with the primary goal to solve a problem).

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BlastocystA transient, hollow ball of 150 to 200 cells formed in early embryonic development that contains the inner cell mass, from which the embryo develops, and an outer layer of cell called the trophoblast, which forms the placenta.

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Bone marrow stromal cellsA general term for non-blood cells in the bone marrow, such as fibroblasts, adipocytes (fat cells) and bone- and cartilage-forming cells that provide support for blood cells. Contained within this population of cells are multipotent bone marrow stromal stem cells that can self-renew and give rise to bone, cartilage, adipocytes and fibroblasts.

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CardiomyocytesThe functional muscle cells of the heart that allow it to beat continuously and rhythmically.

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Clinical translationThe process of using scientific knowledge to design, develop and apply new ways to diagnose, stop or fix what goes wrong in a particular disease or injury; the process by which basic scientific research becomes medicine.

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Clinical trialTests on human subjects designed to evaluate the safety and/or effectiveness of new medical treatments.

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Cord bloodThe blood in the umbilical cord and placenta after child birth. Cord blood contains hematopoietic stem cells, also known as cord blood stem cells, which can regenerate the blood and immune system and can be used to treat some blood disorders such as leukemia or anemia. Cord blood can be stored long-term in blood banks for either public or private use. Also called umbilical cord blood.

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CytoplasmFluid inside a cell, but outside the nucleus.

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DifferentiationThe process by which cells become increasingly specialized to carry out specific functions in tissues and organs.

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Drug discoveryThe systematic process of discovering new drugs.

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Drug screeningThe process of testing large numbers of potential drug candidates for activity, function and/or toxicity in defined assays.

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EmbryoGenerally used to describe the stage of development between fertilization and the fetal stage; the embryonic stage ends 7-8 weeks after fertilization in humans.

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Embryonic stem cells (ESCs)Undifferentiated cells derived from the inner cell mass of the blastocyst; these cells have the potential to give rise to all cell types in the fully formed organism and undergo self-renewal.

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FibroblastA common connective or support cell found within most tissues of the body.

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GlucoseA simple sugar that cells use for energy.

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HematopoieticBlood-forming; hematopoietic stem cells give rise to all the cell types in the blood.

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ImmunomodulatoryThe ability to modify the immune system or an immune response.

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Induced pluripotent stem cells (iPSCs)Embryonic-like stem cells that are derived from reprogrammed, adult cells, such as skin cells. Like ESCs, iPS cells are pluripotent and can self-renew.

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In vitroLatin for in glass. In biomedical research this refers to experiments that are done outside the body in an artificial environment, such as the study of isolated cells in controlled laboratory conditions (also known as cell culture).

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In vivoLatin for within the living. In biomedical research this refers to experiments that are done in a living organism. Experiments in model systems such as mice or fruit flies are an example of in vivo research.

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Islets of LangerhansClusters in the pancreas where insulin-producing beta cells live.

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MaculaA small spot at the back of the retina, densely packed with the rods and cones that receive light, which is responsible for high-resolution central vision.

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Mesenchymal stem cells (MSCs)A term used to describe cells isolated from the connective tissue that surrounds other tissues and organs. MSCs were first isolated from the bone marrow and shown to be capable of making bone, cartilage and fat cells. MSCs are now grown from other tissues, such as fat and cord blood. Not all MSCs are the same and their characteristics depend on where in the body they come from and how they are isolated and grown. May also be called mesenchymal stromal cells.

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Multipotent stem cellsStem cells that can give rise to several different types of specialized cells in specific tissues; for example, blood stem cells can produce the different types of cells that make up the blood, but not the cells of other organs such as the liver or the brain.

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NeuronAn electrically excitable cell that processes and transmits information through electrical and chemical signals in the central and peripheral nervous systems.

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Pancreatic beta cellsCells responsible for making and releasing insulin, the hormone responsible for regulating blood sugar levels. Type I diabetes occurs when these cells are attacked and destroyed by the body's immune system.

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PhotoreceptorsRod or cone cells in the retina that receive light and send signals to the optic nerve, which passes along these signals to the brain.

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PlaceboA pill, injection or other treatment that has no therapeutic benefit; often used as a control in clinical trials to see whether new treatments work better than no treatment.

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Placebo effectPerceived or actual improvement in symptoms that cannot be attributed to the placebo itself and therefore must be the result of the patient's (or other interested person's) belief in the treatment's effectiveness.

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Pluripotent stem cellsStem cells that can become all the cell types that are found in an embryo, fetus or adult, such as embryonic stem cells or induced pluripotent (iPS) cells.

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Preclinical researchLaboratory research on cells, tissues and/or animals for the purpose of discovering new drugs or therapies.

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Precursor cellsAn intermediate cell type between stem cells and differentiated cells. Precursor cells have the potential to give rise to a limited number or type of specialized cells. Also called progenitor cells.

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Progenitor cellsAn intermediate cell type between stem cells and differentiated cells. Progenitor cells have the potential to give rise to a limited number or type of specialized cells and have a reduced capacity for self-renewal. Also called precursor cells.

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Regenerative MedicineAn interdisciplinary branch of medicine with the goal of replacing, regenerating or repairing damaged tissue to restore normal function. Regenerative treatments can include cellular therapy, gene therapy and tissue engineering approaches.

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ReprogrammingIn the context of stem cell biology, this refers to the conversion of differentiated cells, such as fibroblasts, into embryonic-like iPS cells by artificially altering the expression of key genes.

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Retinal pigment epitheliumA single-cell layer behind the rods and cones in the retina that provide support functions for the rods and cones.

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RNARibonucleic acid; it "reads" DNA and acts as a messenger for carrying out genetic instructions.

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Scientific methodA systematic process designed to understand a specific observation through the collection of measurable, empirical evidence; emphasis on measurable and repeatable experiments and results that test a specific hypothesis.

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Self-renewalA special type of cell division in stem cells by which they make copies of themselves.

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Somatic stem cellsScientific term for tissue-specific or adult stem cells.

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Stem cellsCells that have both the capacity to self-renew (make more stem cells by cell division) and to differentiate into mature, specialized cells.

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Stem cell tourismThe travel to another state, region or country specifically for the purpose of undergoing a stem cell treatment available at that location. This phrase is also used to refer to the pursuit of untested and unregulated stem cell treatments.

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TeratomaA benign tumor that usually consists of several types of tissue cells that are foreign to the tissue in which the tumor is located.

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TissueA group of cells with a similar function or embryological origin. Tissues organize further to become organs.

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Tissue-specific stem cellsStem cells that can give rise to the specialized cells in specific tissues; blood stem cells, for example, can produce the different types of cells that make up the blood, but not the cells of other organs such as the liver or the brain. Includes all stem cells other than pluripotent stem cells such as embryonic and induced pluripotent cells. Also called adult or somatic stem cells.

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TotipotentThe ability to give rise to all the cells of the body and cells that arent part of the body but support embryonic development, such as the placenta and umbilical cord.

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Translational researchResearch that focuses on how to use knowledge gleaned from basic research to develop new drugs, treatments or therapies.

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ZygoteThe single cell formed when a sperm cell fuses with an egg cell.

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Stem Cell Glossary

Cuorips, a Japan-based cardiac therapy developer spun out from Osaka University, has secured an undisclosed amount from pharmaceutical firm Daiichi Sankyo.

The investment was made as part of an agreement that gives the corporate an option right for the worldwide commercialisation of Cuorips technology, called iPS-derived cardiomyocyte sheet, a cell therapy for patients suffering from severe heart failure.

The treatment uses induced pluripotent stem (iPS) cells, which can be generated directly from a donors mature cells and differentiated into any organ. It offers an alternative to patients who would otherwise require a heart or artificial heart transplant.

The technology is based on research led by Yoshiki Sawa, professor at the Graduate School of Medicines Department of Cardiovascular Surgery.

Sawa developed the therapy through his participation in the Research Center Network for Realization of Regenerative Medicine, operated by the research organisation Japan Agency for Medical Research and Development.

Cuorips is currently gearing up for clinical research and an investigator-initiated clinical trial.

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Daiichi Sankyo hearts Cuorips - Global University Venturing

Daiichi Sankyo Company has signed an investment contract with Cuorips Inc., an Osaka University spin-off venture to receive an option right concerning the worldwide commercialization of iPS-derived cardiomyocyte (iPS-CM) sheet developed by Cuorips.

The iPS-CM sheet is an allogeneic cell therapy product consisting of cardiomyocyte derived from human iPS cells. Its transplantation is expected to provide improvement of cardiac function and amelioration of heart failure and become a new treatment option for patients with severe heart failure, who have no remedies other than heart transplantation or artificial heart implantation.

Based on the cutting-edge cell therapy research targeting heart diseases, the team at the Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, led by Professor Yoshiki Sawa, has been working on the iPS-CM research and development by participating in the Research Center Network for Realization of Regenerative Medicine, which is run by the Japan Agency for Medical Research and Development (AMED). They are currently preparing for clinical research as well as investigator initiated clinical study.

Cuorips is an Osaka University spin-off venture founded to develop and commercialize iPS-CM sheets based on the research data and technologies developed by the university.

Daiichi Sankyo Group has been conducting research on iPS cell-derived cardiomyocyte and their production, and is currently working on the efficient production process capable for commercial supply.

Daiichi Sankyo and Cuorips are aiming to commercialize iPS-CM sheets as a pioneering treatment for severe heart failure. iPS cells are capable of almost unlimited proliferation and differentiation into any organ, and are expected to be used in the field of cell therapy. There are two types of cell therapy: autologous therapy where the patients own cells are collected, cultured and processed, and allogeneic therapy where a donors cells are collected, cultured and processed.

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Daiichi Sankyo signs Investment contract with Cuorips to commercialize iPS-derived cardiomyocyte sheet - pharmabiz.com

Japanese pharma major Daiichi Sankyo (TYO: 4568) revealed this morning that it has signed an investment contract with Cuorips Inc, an Osaka University spin-off venture to receive an option right concerning the worldwide commercialization of iPS-derived cardiomyocyte (iPS-CM) sheet developed by Cuorips.

The iPS-CM sheet is an allogeneic cell therapy product consisting of cardiomyocyte derived from human iPS cells. Its transplantation is expected to provide improvement of cardiac function and amelioration of heart failure and become a new treatment option for patients with severe heart failure, who have no remedies other than heart transplantation or artificial heart implantation.

Based on the cutting-edge cell therapy research targeting heart diseases, the team at the Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, led by Professor Yoshiki Sawa, has been working on the iPS-CM research and development by participating in the Research Center Network for Realization of Regenerative Medicine, which is run by the Japan Agency for Medical Research and Development (AMED). They are currently preparing for clinical research as well as investigator initiated clinical study.

Cuorips was founded to develop and commercialize iPS-CM sheets based on the research data and technologies developed by the university.

Daiichi Sankyo has been conducting research on iPS cell-derived cardiomyocyte and their production, and is currently working on the efficient production process capable for commercial supply. Daiichi Sankyo and Cuorips are aiming to commercialize iPS-CM sheets as a pioneering treatment for severe heart failure.

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Daiichi Sankyo invests in Osaka University spin-off - The Pharma Letter (registration)