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Archive for the ‘IPS Cell Therapy’ Category

iPS Cell Therapy: Is Japan the Market Leader?

Although there are key players in markets like the U.S., Australia, and the EU, Japan continues to accelerates its position as a hub for induced pluripotent stem cell (iPS cell) therapy with generous funding, acquisitions, and strategic partnerships.

Pluripotent stem cells are cells that are capable of developing into any type of cell or tissue in the human body. These cells have the capability to replicate and help in repairing damaged tissues within the body. In 2006, the Japanese scientist Shinya Yamanaka demonstrated that an ordinary cell can be turned into a pluripotent cell by genetic modification. These genetically reprogrammed cells are known as induced pluripotent cells, also called iPS cells or iPSCs.

An induced pluripotent stem cell (iPS cell) is a type of pluripotent stem cell that has the capacity to divide indefinitely and create any cell found within the three germ layers of an organism. These layers include the ectoderm (cells giving rise to the skin and nervous system), endoderm (cells forming gastrointestinal and respiratory tracts, endocrine gland, liver, and pancreas), and mesoderm (cells forming bones, cartilage, most of the circulatory system, muscles, connective tissues, and other related tissues.).

iPS cells have significant potential for therapeutic applications. For autologous applications, the cells are extracted from the patients own body, making them genetically identical to the patient and eliminating the issues associated with tissue matching and tissue rejection.

iPS cells have the potential to be used to treat a wide range of diseases, including diabetes, heart diseases, autoimmune diseases, and neural complications, such as Parkinsons disease, Alzheimers disease.

Over the past few years, Japan has accelerated its position as a hub for regenerative medicine research, largely driven by support from Prime Minister Shinzo Abe who has identified regenerative medicine and cellular therapy as key to the Japans strategy to drive economic growth.

The Prime Minister has encouraged a growing range of collaborations between private industry and academic partners through an innovative legal framework approved last fall.

He has also initiated campaigns to drive technological advances in drugs and devices by connecting private companies with public funding sources. The result has been to drive progress in both basic and applied research involving induced pluripotent stem cells (iPS cells) and related stem cell technologies.

2013 was a landmark year in Japan, because it saw the first cellular therapy involving transplant of iPS cells into humans initiated at the RIKEN Center in Kobe, Japan.[1]Led by Masayo Takahashi of theRIKEN Center for Developmental Biology (CDB).Dr. Takahashi and her team wereinvestigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration.

To speed things along, RIKEN did not seek permission for a clinical trial involving iPS cells, but instead applied for a type of pretrial clinical research allowed under Japanese regulations.The RIKEN Center is Japans largest, most comprehensive research institution, backed by both Japans Health Ministry and government.

This pretrial clinical research allowed the RIKEN research team to test the use of iPS cells for the treatment of wet-type age-related macular degeneration (AMD) on a very small scale, in only a handful of patients.Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanakas team identified two small genetic changes in the patients iPSCs and the retinal pigment epithelium (RPE) cells derived from them.

However, in June 2016 RIKEN Institute announced that it would be resuming the clinical study involving the use of iPSC-derived cellsin humans.According to theJapan Times, this second attempt at the clinical studyis using allogeneic rather than autologous iPSC-derived cells, because of the greater cost and time efficiencies.

Specifically,the researchers will be developing retinal tissues from iPS cells supplied by Kyoto Universitys Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka.

Japan has a unique affection for iPS cells, as the cells were originally discovered by the Japanese scientist, Shinya Yamanaka of Kyoto University. Mr. Yamanaka was awarded the Nobel Prize in Physiology or Medicine for 2012, an honor shared jointly with John Gurdon, for the discovery that mature cells can be reprogrammed to become pluripotent.

In addition, Japans Education Ministry said its planning to spend 110 billion yen ($1.13 billion) on induced pluripotent stem cell research during the next 10 years, and the Japanese parliament has been discussing bills that would speed the approval process and ensure the safety of such treatments.[3]

In April, Japanese parliament even passed a law calling for Japan to make regenerative medical treatments like iPSC technology available for its citizens ahead of the rest of the world.[4] If those forces were not enough, Masayo Takahashi of the RIKEN Center for Developmental Biology in Kobe, Japan, who is heading the worlds first clinical research using iPSCs in humans, was also chosen by the journal Natureas one of five scientists to watch in 2014.[5]

Clearly, Japan is the global leader in iPS cell technologies and therapies. However, progress with stem cells has not been without setbacks within Japan, including a recent scandal at the RIKEN Institute that involved falsely manipulated research findings and a hold on the first clinical trial involving transplant of an iPS cell product into humans.

Nonetheless, Japan has emerged from these troubles to become the most liberalized nation pursuing the development of iPS cell products and services.

iPS cells represent one of the most promising advances within the field of stem cell research, because of their diverse ability to differentiate into any of the approximately 200 cell types that compose the human body.

Even though there is growing evidence to support the safety of iPS cells within cell therapy applications,some people remain concerned that patients who receive implants of iPS derived cells might be at risk of cancer, as genetic manipulation is required to create the cell type.

In a world-first, Cynata Therapeutics (ASX:CYP) received approval in September 2016 to launch a clinical trial in the UK with the worlds first first formal clinical trial of an allogeneic iPSC-derived cell product, which it calls CYP-001.The study involves centers in both the UK and Australia.

In this landmark trial, the Australian regenerative medicine company is testing an iPS cell-derived mesenchymal stem cell (MSC) product for the treatment of Graft-vs-Host-Disease (GvHD).Not surprisingly, the Japanese conglomerate Fujifilm is also involved with this historic trial.

Headquartered in Tokyo, Fujifilm is one of the largest players in regenerative medicine field and has invested significantly into stem cells through their acquisition of Cellular Dynamics International (CDI). Additionally, Fujifilm has invested in Japan Tissue Engineering Co. Ltd. (J-Tec), giving it a broad base in regenerative medicine across multiple therapeutic areas.

For a young company like Cynata, having validation from an industry giant like Fujifilm is a huge boost. As stated by Cynata CEO, Dr. Ross Macdonald, The decision by Fujifilm confirms that our technology is very exciting in their eyes. It is a useful yardstick for other investors as well. Of course, the effect of the relationship with Fujifilm on our balance sheet is also important.

If Fujifilm exercises their option to license Cynatas GvHD product, then the costs of the product and commercialization will become the responsibility of Fujifilm. Cynata would also receive milestone payments from Fujifilm of approximately $60M AUS and a double-digit royalty payment.

Cynata was also the first to scale-up manufacture of an allogeneic cGMP iPS celll line. It sourced the cell line from Cellular Dynamics International (CDI) when CDI was still an independent company listed on NASDAQ. In April 2015, CDI was subsequently acquired by Fujifilm, who as mentioned, is a major shareholder in Cynata and its strategic partner for GvHD.

Although Cynata is showing promising early-stage data from its GvHD trial, methods for commercializing iPS cells are still being explored and clinical studies investigating iPS cells remain extremely low in number.

Footnotes[1] Dvorak, K. (2014).Japan Makes Advance on Stem-Cell Therapy [Online]. Available at: http://online.wsj.com/news/articles/SB10001424127887323689204578571363010820642. Web. 14 Apr. 2015.[2] Note: In the United States, some patients have been treated with retina cells derived from embryonic stem cells (ESCs) to treat macular degeneration. There was a successful patient safety test for this stem cell treatment last year that was conducted at the Jules Stein Eye Institute in Los Angeles. The ESC-derived cells used for this study were developed by Advanced Cell Technology, Inc, a company located in Marlborough, Massachusetts.[3] Dvorak, K. (2014).Japan Makes Advance on Stem-Cell Therapy [Online]. Available at: http://online.wsj.com/news/articles/SB10001424127887323689204578571363010820642. Web. 8 Apr. 2015.[4] Ibid.[5] Riken.jp. (2014).RIKEN researcher chosen as one of five scientists to watch in 2014 | RIKEN [Online]. Available at: http://www.riken.jp/en/pr/topics/2014/20140107_1/. Web. 14 Apr. 2015.

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iPS Cell Therapy: Is Japan the Market Leader?

Cell Therapy Companies – BioInformant

Cell therapy companies have been rapidly populating over the past few years, making the cell therapy market a high-value, fast-growth market. Key drivers for the market include high rates of cell therapy clinical trials, accelerated pathways for cell therapy product approvals, new technologies to support cell therapy manufacturing, and the potential for cell therapies to revolutionize healthcare.

Additionally, the market gained recent momentum when the Swiss pharmaceutical giant Novartis made history as the first company to win FDA approval for a CAR-T cell therapy in the U.S. in August 2017 (Kymriah).In October 2017, Kite Pharma became the second company to get FDA approval of a CAR-T cell therapy (Yescarta).

These historic events demonstrate to investors, the public and funding providers alike that cell therapy is a market that has emerged, no longer one that is evolving in the future.Today, there are nearly 40 companies developing redirected T cells or NK cells for therapeutic use. There are nearly 70 companies developing stem cell therapeutics (45% of all cell therapy companies). Finally, direct cell reprogramming is gaining popularity as a therapeutic strategy, because of its safety and efficacy advantages.

Because of this rapid market growth, BioInformant has released a global database featuring 150+ cell therapy companies worldwide. It was originally developed in-house for our own purposes, but we have had more and moreclients requesting access to it. For this reason, we updated and expanded it with additional company details. Now, we have officially launched it to the public.

Cell Therapy Companies CAR-T, CAR-NK, Stem Cells, Direct Reprogramming

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Cell Therapy Companies – BioInformant

iPS Cell Therapy – Parent Project Muscular Dystrophy

iPS Cells and Therapeutic Applications for Duchenne

We are currently in the optimization/validation phase of pre-clinical development.

This research is being done in the lab of Dr. Rita Perlingeiro at the University of Minnesota, in partnership with the University of Minnesota Center for Translational Medicine and the Molecular and Cellular Therapeutics Facility. This work is currently funded by the Department of Defense (DoD).

Induced pluripotent stem cells (iPS) are adult cells that have been reprogrammed to an embryonic stem cell-like state.There has been tremendous excitement for the therapeutic potential of iPS cells in treating genetic diseases. Our current research builds on our successful proof-of-principle studies for Duchenne performed with mouse wild-type and dystrophic iPS cells as well as control (healthy) human iPS cells. These studies demonstrate equivalent functional myogenic engraftment to that observed with their embryonic counterparts following their transplantation into dystrophic mice.

Our goal now is to apply this technology to clinical grade GMP-compliant iPS cells, and generate a cell product, iPS-derived myogenic progenitors, that can be delivered to muscular dystrophy patients.

Optimization of methodology, characterization of cell product, scalability with GMP-compliant method, followed by safety and efficacy studies. Once these have been achieved, we will be ready to move into a clinical trial.

2-3 years (it depends largely on how much funding we have available to conduct these studies).

University of Minnesota

In the first phase, adults with confirmed diagnosis of Duchenne (> 18 years old).

You can learn more about this research at the website for Dr. Perlingeiros lab: http://www.med.umn.edu/lhi/research/PerlingeiroLab/index.htm

http://www.ClinicalTrials.gov will post all clinical trials once they are actively recruiting patients.

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iPS Cell Therapy – Parent Project Muscular Dystrophy

New Jersey Stem Cell Therapy – Stem Cell Center Of NJ

COPD

Over 32 million Americans suffer from chronic obstructive pulmonary disease (also known as COPD). COPD is a progressive lung disease, however regenerative medicine, such as lung regeneration therapies using stem cells are showing potential for COPD by encouraging tissue repair and reducing inflammation to the diseased lung tissue.

Following up with stem cell therapy and exome therapy immediately in the first 36 to 48 hours after stroke symptoms surface has proven to be crucial to long-term recovery and regaining mobility again. Cell therapy also calms post-stroke inflammation in the body, and reduces risk of serious infections.

Parkinsons is a neurodegenerative brain disorder caused by the gradual loss of dopamine-producing cells in the brain. It afflicts more than 1 million people in the U.S., and currently, there is no known cure. Stem cell therapies have been showing incredible progress. Using induced pluripotent stem (iPS) cells, a mature cell can be reprogrammed into an embryonic-like, healthy and highly-functioning state, which has the potential to become a dopamine-producing cell in the brain.

A thick, full head of hair is possible, naturally! Stem cell and exosome therapy promotes healing from within to naturally stimulate hair follicles, which encourages new hair growth. Using your own stem cells, Platelet Rich Plasma (PRP) and exosomes, you can regrow your own healthy, thick hair naturally and restore your confidence!

Erectile Dysfunction (ED) is the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Regenerative medicine offers a non-surgical option that commonly uses the patients own stem cells, exosomes, and other sources of growth factors to regenerate healthy tissue to improve performance and sensation.

If chronic joint pain is derailing your active lifestyle, then youre not alone. Regenerative medicine offers a non-surgical option that commonly uses the patients own stem cells, exosomes, and other sources of growth factors to reduce inflammation, promote natural healing and regenerate healthy tissue surrounding the joint for relief.

Multiple Sclerosis (MS) affects 400,000 people in the U.S., and occurs when the body has an abnormal immune system response and attacks the central nervous system. Regenerative medicine now offers treatment for MS with stem cell therapy, which is an exciting and rapidly developing field of therapy. Stem cells work to repair damaged cells these new cells can become replacement cells to restore normal functionality.

Spinal cord injuries are as complex as they are devastating. Today, cellular treatments, usually a combination of therapies, such as stem cell, Platelet Rich Plasma (PRP) and exosome therapy with growth factors are showing promise in contributing to spinal cord repair and reducing inflammation at the site of injury.

If you have chronic nerve injury pain that doesnt fade, your health care provider may recommend surgery to reverse the damage. However, regenerative medicine offers a non-surgical option to repair damaged tissue and reduce inflammation at the site of injury. Stem cell therapy commonly uses the patients own stem cells, exosomes, and other sources of growth factors to regenerate healthy tissue.

Neuropathy also called peripheral neuropathy occurs when nerves are damaged and cant send messages from the brain and spinal cord to the muscles, skin and other parts of the body. Simply put, the two areas stop communicating. Stem cell and exosome therapies treat damaged nerves affected by neuropathy, and they have the ability to replicate and create new, healthy cells, while repairing damaged tissue.

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New Jersey Stem Cell Therapy – Stem Cell Center Of NJ

Stem Cell Therapy for Duchenne Muscular Dystrophy …

Duchenne muscular dystrophy (DMD) is the most common and serious form of muscular dystrophy. One out of every 3500 boys is born with the disorder, and it is invariably fatal. Until recently, there was little hope that the widespread muscle degeneration that accompanies this disease could be combated.

However, stem cell therapy now offers that hope. Like other degenerative disorders, DMD is the result of loss of cells that are needed for correct functioning of the body. In the case of DMD, a vital muscle protein is mutated, and its absence leads to progressive degeneration of essentially all the muscles in the body.

To begin to approach a therapy for this condition, we must provide a new supply of stem cells that carry the missing protein that is lacking in DMD. These cells must be delivered to the body in such a way that they will engraft in the muscles and produce new, healthy muscle tissue on an ongoing basis.

We now possess methods whereby we can generate stem cells that can become muscle cells out of adult cells from skin or fat by a process known as reprogramming. Reprogramming is the addition of genes to a cell that can dial the cell back to becoming a stem cell. By reprogramming adult cells, together with addition to them of a correct copy of the gene that is missing in DMD, we can potentially create stem cells that have the ability to create new, healthy muscle cells in the body of a DMD patient. This is essentially the strategy that we are developing in this proposal.

We start with mice that have a mutation in the same gene that is affected in DMD, so they have a disease similar to DMD. We reprogram some of their adult cells, add the correct gene, and grow the cells in incubators in a manner that will produce muscle stem cells. The muscle stem cells can be identified and purified by using an instrument that detects characteristic proteins that muscles make.

The corrected muscle stem cells are transplanted into mice with DMD, and the ability of the cells to generate healthy new muscle tissue is evaluated. Using the mouse results as a guide, a similar strategy will then be pursued with human cells, utilizing cells from patients with DMD. The cells will be reprogrammed, the correct gene added, and the cells grown into muscle stem cells. The ability of these cells to make healthy muscle will be tested by injection into mice with DMD that are immune-deficient, so they will accept a graft of human cells.

In order to make this process into something that could be used in the clinic, we will develop standard procedures for making and testing the cells, to ensure that they are effective and safe. In this way, this project could lead to a new stem cell therapy that could improve the clinical condition of DMD patients. If we have success with DMD, similar methods could be used to treat other degenerative disorders, and perhaps even some of the degeneration that occurs during normal aging

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Stem Cell Therapy for Duchenne Muscular Dystrophy …

Lung Institute | Stem Cell Research Study for Lung Disease

The Problem with Chronic Pulmonary Diseases

Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disorder that often occurs as a result of prolonged cigarette smoking, second-hand smoke, and polluted air or working conditions. COPD is the most prevalent form of chronic lung disease. The physiological symptoms of COPD include shortness of breath (dyspnea), cough, and sputum production, exercise intolerance and reduced Quality of Life (QOL). These signs and symptoms are brought about by chronic inflammation of the airways, which restricts breathing. When fibrotic tissues contract, the lumen is narrowed, compromising lung function. As histological studies confirm, airway fibrosis and luminal narrowing are major features that lead to airflow limitation in COPD1-3.

Today, COPD is a serious global health issue, with a prevalence of 9-10% of adults aged 40 and older4. And the prevalence of the disease is only expected to rise. Currently COPD accounts for 27% of tobacco related deaths and is anticipated to become the fourth leading cause of death worldwide by 2030 5. Today, COPD affects approximately 600 million individualsroughly 5% of the worlds population 6. Despite modern medicine and technological advancements, there is no known cure for COPD.

The difficulty in treating COPD and other lung diseases rests in the trouble of stimulating alveolar wall formation15. Until recently, treatment has been limited by two things: a lack of understanding of the pathophysiology of these disease processes on a molecular level and a lack of pharmaceutical development that would affect these molecular mechanisms. This results in treatment focused primarily in addressing the symptoms of the disease rather than healing or slowing the progression of the disease itself.

The result is that there are few options available outside of bronchodilators and corticosteroids7. Although lung transplants are performed as an alternative option, there is currently a severe shortage of donor lungs, leaving many patients to die on waiting lists prior to transplantation. Lung transplantation is also a very invasive form of treatment, commonly offering poor results, a poor quality of life with a 5-year mortality rate of approximately 50%, and a litany of health problems associated with lifelong immunosuppression13.

However, it has been shown that undifferentiated multipotent endogenous tissue stem cells (cells that have been identified in nearly all tissues) may contribute to tissue maintenance and repair due to their inherent anti-inflammatory properties. Human mesenchymal stromal cells have been shown to produce large quantities of bioactive factors including cytokines and various growth factors which provide molecular cueing for regenerative pathways. This affects the status of responding cells intrinsic in the tissue 18. These bioactive factors have the ability to influence multiple immune effector functions including cell development, maturation, and allo-reactive T-cell responses 19. Although research on the use of autologous stem cells (both hematopoietic and mesenchymal) in regenerative stem cell therapy is still in the early stages of implementation, it has shown substantive progress in treating patients with few if any adverse effects.

The Lung Institute (LI) provided treatment by harvesting autologous stem cells (hematopoietic stem cells and mesenchymal stromal cells) by withdrawing adipose tissue (fat), bone marrow or peripheral blood. These harvested cells are isolated and concentrated, and along with platelet-rich plasma, are then reintroduced into the body and enter the pulmonary vasculature (vessels of the lungs) where cells are trapped in the microcirculation (the pulmonary trap). Alternatively, nebulized stem cells are reintroduced through the airways in patients who have undergone an adipose (fat tissue) treatment.

Individuals diagnosed with COPD were tracked by the Lung Institute to measure the effects of treatment via either the venous protocol or adipose protocol on both their pulmonary function as well as their Quality of Life.

All PFTs were performed according to national practice guideline standards for repeatability and acceptability8-10. On PFTs, pre-treatment data was collected through on-site testing or through previous medical examinations by the patients primary physician (if done within two weeks). The test was then repeated by their primary physician 6 months after treatment.*

* Due to the examination information required from primary physicians, only 25 out of 100 patients are reflected in the PFT data.

Patients with progressive COPD will typically experience a steady decrease in their Quality of Life. Given this development, a patients Quality of Life score is frequently used to define additional therapeutic effects, with regulatory authorities frequently encouraging their use as primary or secondary outcomes17.

On quality of life testing, data was collected through the implementation of the Clinical COPD Questionnaire (CCQ) based survey17. The survey measured the patients self-assessed quality of life on a 0-6 scale, with adverse Quality of Life correlated in ascending numerical order. It was implemented in three stages: pre-treatment, 3-months post-treatment, and 6-months post-treatment. The survey measured two distinct outcomes: the QLS score, which measured the patients self-assessed quality of life score, and the QIS, a percentage-based measurement determining the proportion of patients within the sample that experienced QLS score improvements.

Over the duration of six months, the results of 100 patients treated for COPD through venous and adipose based therapies were tracked by the Lung Institute in order to measure changes in pulmonary function and any improvement in Quality of Life.

Of the 100 patients treated by the Lung Institute, 64 were male (64%) and 36 were female (36%). Ages of those treated range from 55-88 years old with an average age of 71. Throughout the study, 82 (82%) were treated with venous derived stem cells, while 18 (18%) were treated from stem cells derived from adipose tissue.

* The survey measured the patients self-assessed quality of life on a 0-6 scale, with adverse Quality of Life correlated in ascending numerical order.

Over the course of the study, the patient group averaged an increase of 35.5% to their Quality of Life (QLS) score within three months of treatment. While in the QIS, 84% of all patients found that their Quality of Life score had improved within three months of treatment (figure 1.3).

Within the PFT results, 48% of patients tested saw an increase of over 10% to their original pulmonary function with an average increase of 16%. During the three to six month period after treatment, patients saw a small decline in their progress, with QLS scores dropping from 35.5% to 32%, and the QIS from 84% to 77%.Fletcher and Petos work shows that patient survival rate can be improved through appropriate or positive intervention14 (figure 1.4). It remains to be seen if better quality of life will translate to longevity, but if one examines what factors allow for improved quality of life such as improvement in oxygen use, exercise tolerance, medication use, visits to the hospital and reduction in disease flare ups then one can see that quality of life improves in association with clinical improvement.

Currently the most utilized options for treating COPD are bronchodilator inhalers with or without corticosteroids and lung transplant each has downsides. Inhalers are often used incorrectly11, are expensive over time, and can only provide temporary relief of symptoms. Corticosteroids, though useful, have risk of serious adverse side effects such as infections, blood sugar imbalance, and weight gain to name a few 16. Lung transplants are expensive, have an adverse impact on quality of life and have a high probability of rejection by the body the treatment of which creates a new set of problems for patients. In contrast, initial studies of stem cells treatments show efficacy, lack of adverse side effects and may be used safely in conjunction with other treatments.

Through the data collected by the Lung Institute, developing methodologies for this form of treatment are quickly taking place as other entities of the medical community follow suit. In a recent study of regenerative stem cell therapy done by the University of Utah, patients exhibited improvement in PFTs and oxygen requirement compared to the control group with no acute adverse events12. Through the infusion of stem cells derived from the patients own body, stem cell therapy minimizes the chance of rejection to the highest degree, promotes healing and can improve the patients pulmonary function and quality of life with no adverse side effects.

Although more studies using a greater number of patients is needed to further examine objective parameters such as PFTs, exercise tests, oxygen, medication use and hospital visits, larger sample sizes will also help determine if one protocol is more beneficial than others. With deeper research, utilizing economic analysis along with longer-term follow up will answer questions on patient selection, the benefits of repeated treatments, and a possible reduction in healthcare costs for COPD treatment.

The field of Cellular Therapy and Regenerative Medicine is rapidly advancing and providing effective treatments for diseases in many areas of medicine.The Lung Institutes strives to provide the latest in safe, effective therapy for chronic lung disease and maintain a leadership role in the clinical application of these technologies.

In a landscape of scarce options and rising costs, the Lung Institute believes that stem cell therapy is the future of treatment for those suffering from COPD and other lung diseases. Although data is limited at this stage, we are proud to champion this form of treatment while sharing our findings.

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Lung Institute | Stem Cell Research Study for Lung Disease

Stem Cell Center Of NJ – New Jersey Stem Cell Therapy

COPD

Over 32 million Americans suffer from chronic obstructive pulmonary disease (also known as COPD). COPD is a progressive lung disease, however regenerative medicine, such as lung regeneration therapies using stem cells are showing potential for COPD by encouraging tissue repair and reducing inflammation to the diseased lung tissue.

Following up with stem cell therapy and exome therapy immediately in the first 36 to 48 hours after stroke symptoms surface has proven to be crucial to long-term recovery and regaining mobility again. Cell therapy also calms post-stroke inflammation in the body, and reduces risk of serious infections.

Parkinsons is a neurodegenerative brain disorder caused by the gradual loss of dopamine-producing cells in the brain. It afflicts more than 1 million people in the U.S., and currently, there is no known cure. Stem cell therapies have been showing incredible progress. Using induced pluripotent stem (iPS) cells, a mature cell can be reprogrammed into an embryonic-like, healthy and highly-functioning state, which has the potential to become a dopamine-producing cell in the brain.

A thick, full head of hair is possible, naturally! Stem cell and exosome therapy promotes healing from within to naturally stimulate hair follicles, which encourages new hair growth. Using your own stem cells, Platelet Rich Plasma (PRP) and exosomes, you can regrow your own healthy, thick hair naturally and restore your confidence!

Erectile Dysfunction (ED) is the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Regenerative medicine offers a non-surgical option that commonly uses the patients own stem cells, exosomes, and other sources of growth factors to regenerate healthy tissue to improve performance and sensation.

If chronic joint pain is derailing your active lifestyle, then youre not alone. Regenerative medicine offers a non-surgical option that commonly uses the patients own stem cells, exosomes, and other sources of growth factors to reduce inflammation, promote natural healing and regenerate healthy tissue surrounding the joint for relief.

Multiple Sclerosis (MS) affects 400,000 people in the U.S., and occurs when the body has an abnormal immune system response and attacks the central nervous system. Regenerative medicine now offers treatment for MS with stem cell therapy, which is an exciting and rapidly developing field of therapy. Stem cells work to repair damaged cells these new cells can become replacement cells to restore normal functionality.

Spinal cord injuries are as complex as they are devastating. Today, cellular treatments, usually a combination of therapies, such as stem cell, Platelet Rich Plasma (PRP) and exosome therapy with growth factors are showing promise in contributing to spinal cord repair and reducing inflammation at the site of injury.

If you have chronic nerve injury pain that doesnt fade, your health care provider may recommend surgery to reverse the damage. However, regenerative medicine offers a non-surgical option to repair damaged tissue and reduce inflammation at the site of injury. Stem cell therapy commonly uses the patients own stem cells, exosomes, and other sources of growth factors to regenerate healthy tissue.

Neuropathy also called peripheral neuropathy occurs when nerves are damaged and cant send messages from the brain and spinal cord to the muscles, skin and other parts of the body. Simply put, the two areas stop communicating. Stem cell and exosome therapies treat damaged nerves affected by neuropathy, and they have the ability to replicate and create new, healthy cells, while repairing damaged tissue.

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Stem Cell Center Of NJ – New Jersey Stem Cell Therapy

Pluripotent Stem CellBased Therapy for Heart Disease …

Five million people in the U.S. suffer with heart failure, resulting in ~60,000 deaths/year at a cost of $30 billion/year. Heart failure occurs when the heart is damaged and becomes unable to meet the demands placed on it. Unlike other organs, the heart is unable to fully repair itself after injury. One of the common causes for the development of heart damage is a heart attack. After a myocardial infarction (heart attack), irreversible loss of contracting heart muscle cells occurs, resulting in scar formation and subsequently heart failure. Current therapies designed to treat heart attack patients in the acute setting include medical therapies and catheter-based technologies that aim to open the blocked coronary arteries with the hope of salvaging as much of the jeopardized heart muscle cells as possible. Unfortunately, despite advances over the past 2 decades, it is rarely possible to rescue the at-risk heart muscle cells from some degree of irreversible injury and death.

Attention has turned to new methods of treating heart attack and heart failure patients in both the acute and chronic settings after their event. Heart transplantation remains the ultimate approach to treating end-stage heart failure patients but this therapy is invasive, costly, some patients are not candidates for transplantation given their other co-morbidities, and most importantly, there are not enough organs for transplanting the increasing number of patients who need this therapy. As such, newer therapies are needed to treat the millions of patients with debilitating heart conditions. Recently, it has been discovered that stem cells may hold therapeutic potential for these patients. Experimental studies in animals have revealed encouraging results when pluripotent stem cells are introduced into the heart around areas of myocardial infarction. These therapies appear to result in improvement in the contractile function of the heart.

However, numerous questions remain unanswered concerning the use of pluripotent stem cells as therapy for patients with heart attack and heart failure. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells grow and divide indefinitely while maintaining the potential to develop into many tissues of the body, including heart muscle. They provide an unprecedented opportunity to both study human heart muscle in culture in the laboratory, and advance the possibility of their use in therapy for damaged heart muscle. We have developed methods for identifying and isolating specific types of human ES and iPS cells, stimulating them to become human heart muscle cells, and delivering these into the hearts of rodents that have had a heart attack. This research will refine and advance such approaches in small and large animals, develop clinical grade cells for use, and ultimately initiate clinical trials for patients suffering from heart disease.

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Pluripotent Stem CellBased Therapy for Heart Disease …

Stem Cell Therapy & Treatment – Diseases and Conditions

Mesenchymal stem cells (MSCs) are found in the bone marrow and are responsible for bone and cartilage repair. On top of that, they can also produce fat cells. Early research suggesting that MSCs could differentiate into many other cell types and that they could also be obtained from a wide variety of tissues other than bone marrow have not been confirmed. There is still considerable scientific debate surrounding the exact nature of the cells (which are also termed Mesenchymal stem cells) obtained from these other tissues.

As of now, no treatments using mesenchymal stem cells are proven to be effective. There are, however, some clinical trials investigating the safety and effectiveness of MSC treatments for repairing bone or cartilage. Other trials are investigating whether MSCs might help repair blood vessel damage linked to heart attacks or diseases such as critical limb ischaemia, but it is not yet clear whether these treatments will be effective.

Several other features of MSCs, such as their potential effect on immune responses in the body to reduce inflammation to help treat transplant rejection or autoimmune diseases are still under thorough investigation. It will take numerous studies to evaluate their therapeutic value in the future.

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Stem Cell Therapy & Treatment – Diseases and Conditions

Stem Cell-Based Therapy for Cartilage Regeneration and …

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.

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Cell Replacement Therapy For Parkinsons Disease And The …

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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The Promise of Induced Pluripotent Stem Cells (iPSCs …

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 …

Center for Embryonic Cell and Gene Therapy | Center for …

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 …

Monkeys With Parkinson’s Disease Successfully Treated With Human Stem Cell Transplants – 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

iPS Cell-based Neuron Therapy Benefits Monkeys With Parkinson’s – ReliaWire

Monkeys with Parkinsons disease symptoms show significant improvement over two years after being transplanted neurons prepared from human induced pluropontent stem cells, scientists at the Center for iPS Cell Research and Application (CiRA), Kyoto University, report. One of the last steps before treating patients with an experimental cell therapy for the brain is confirmation that the therapy works in monkeys.

Parkinsons 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.

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,

said Professor Jun Takahashi, a neurosurgeon specializing in Parkinsons disease, who plans to use DA neurons made from iPS cells to treat patients.

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 Parkinsons 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 survive, 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. The study is the teams answer to bring iPS cells to clinical settings, said Takahashi.

Tetsuhiro Kikuchi, Asuka Morizane, Daisuke Doi, Hiroaki Magotani, Hirotaka Onoe, Takuya Hayashi, Hiroshi Mizuma, Sayuki Takara, Ryosuke Takahashi, Haruhisa Inoue, Satoshi Morita, Michio Yamamoto, Keisuke Okita, Masato Nakagawa, Malin Parmar, Jun TakahashiHuman iPS cell-derived dopaminergic neurons function in a primate Parkinsons disease modelNature, 2017; 548 (7669): 592 DOI: 10.1038/nature23664

Image: Annie Cavanagh / Wellcome Images

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iPS Cell-based Neuron Therapy Benefits Monkeys With Parkinson’s – ReliaWire

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

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

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.

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

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

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.

Original post:
Xeno-free Cell Culture Medium for Regenerative Medicine Research – Technology Networks

Reprogrammed cells relieve Parkinson’s symptoms in trials – Nature.com

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 embryonic-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.

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Reprogrammed cells relieve Parkinson’s symptoms in trials – Nature.com

Wasteful spending on medical public works – The Japan Times

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

For Immune System Stem Cell Studies, Mice Aren’t Enough – Science 2.0

If mouse studies were transferable to humans, we’d have cured every disease thousands of times. That is the big reason why you shouldn’t accept scaremongering about the chemical of the week in the New York Times, or claims about Miracle Vegetables in the Washington Post.

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 their side. That’s not to say mouse studies are not valuable, they eliminate a lot of bad products, and in some instances mouse models are good analogues of humans, like in HIV infection, but a new paper reveals what chemists have long known: When it comes to the immune system rats are not little people, even “humanized” mice whichhave been engineered to have a human, rather than a murine, immune system.

These animals have been used for decades to study things like the immune response to the transplantation of pancreatic islet cells for diabetes and skin grafts for burn victims. But unlike what would occur in a human patient, the humanized mice are unable to robustly reject the transplantation of genetically mismatched human stem cells. As a result, they can’t be used to study the immunosuppressive drugs that patients will likely require after transplant. The researchers conclude that the humanized mouse model is not suitable for studying the human immune response to transplanted stem cells or cells derived from them.

“In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would,” said Joseph Wu, MD, PhD, director of Stanford University School of Medicine’s Cardiovascular Institute and professor of cardiovascular medicine and of radiology. “We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can’t do that with these animals.”

The researchers write in Cell Reports that they were studying pluripotent stem cells, which can become any tissue in the body. They tested the animals’ immune response to human embryonic stem cells, which are naturally pluripotent, and to induced pluripotent stem cells. Although iPS cells can be made from a patient’s own tissues, future clinical applications will likely rely on pre-screened, FDA-approved banks of stem cell-derived products developed for specific clinical situations, such as heart muscle cells to repair tissue damaged by a heart attack, or endothelial cells to stimulate new blood vessel growth. Unlike patient-specific iPS cells, these cells would be reliable and immediately available for clinical use. But because they won’t genetically match each patient, it’s likely that they would be rejected without giving the recipients immunosuppressive drugs.

The authors found that two varieties of humanized mice were unable to completely reject unrelated human embryonic stem cells or iPS cells, despite the fact that some human immune cells homed to and were active in the transplanted stem cell grafts. In some cases, the cells not only thrived, but grew rapidly to form cancers called teratomas. In contrast, mice with unaltered immune systems quickly dispatched both forms of human pluripotent stem cells.

The researchers obtained similar results when they transplanted endothelial cells derived from the pluripotent stem cells.

A new mouse model

To understand more about what was happening, they created a new mouse model similar to the humanized mice. Instead of reconstituting the animals’ nonexistent immune systems with human cells, however, they used immune and bone marrow cells from a different strain of mice. They then performed the same set of experiments again.

Unlike the humanized mice, these new mice robustly rejected human pluripotent stem cells as well as mouse stem cells from a genetically mismatched strain of mice. In other words, their newly acquired immune systems appeared to be in much better working order.

Although more research needs to be done to identify the cause of the discrepancy between the two types of animals, the researchers speculate it may have something to do with the complexity of the immune system and the need to further optimize the humanized mouse model to perhaps include other types of cells or signaling molecules. In the meantime, they are warning other researchers of potential pitfalls in using this model to screen for immunosuppressive drugs that could be effective after human stem cell transplants.

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For Immune System Stem Cell Studies, Mice Aren’t Enough – Science 2.0

An Experts Perspective on Accelerated Pathways for Cell …

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.

Related

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An Experts Perspective on Accelerated Pathways for Cell …

Daiichi Sankyo hearts Cuorips – Global University Venturing

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

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)

Affimed Therapeutics’ (AFMD) CEO Adi Hoess on Q2 2017 Results – Earnings Call Transcript – Seeking Alpha

Affimed Therapeutics (NASDAQ:AFMD)

Q2 2017 Earnings Conference Call

August 1, 2017 8:30 AM ET

Executives

Anca Alexandru Head of Communications

Adi Hoess Chief Executive Officer

Florian Fischer Chief Financial Officer

Analysts

Maury Raycroft Jefferies

Do Kim BMO Capital Markets

Michael Schmidt Leerink

Peter Lawson SunTrust

Operator

Good day and welcome to the Affimed Second Quarter 2017 Financial Results and Corporate Update Conference Call. Todays conference is being recorded. At this time, I would like to turn the conference over to Anca Alexandru. Please go ahead.

Anca Alexandru

Thanks. I would like to welcome you to our investor and analyst call on the results for the second quarter of 2017. On the call with me today are Adi Hoess, CEO of Affimed, who will present the corporate update; and Florian Fischer, Affimeds CFO, who will walk you through the financials.

Slide 2, before we start, please note that this call and the Q&A session contains forward-looking statements, including statements regarding our future financial condition, business strategy, and our plans and objectives for our future operations.

These statements represent our beliefs and assumptions only as of the date of this discussion. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.

These forward-looking statements are subject to risks and uncertainties and actual results may differ materially from those expressed or implied in the forward-looking statements due to various factors including, but not limited to those identified under the section entitled risk Factors in our filings with the SEC and those identified under the section entitled cautionary statements regarding forward-looking statements in our Form 6-K filed with the SEC earlier today.

Thank you for your understanding. I will now hand the call over to our CEO, Adi Hoess, who will provide the corporate update.

Adi Hoess

Thanks a lot, Anca. Affimed has developed an immune cell engager and our clinical and preclinical pipeline based on tetravalent bi and trispecificantibody formats. Were an industry leader in NK cell engagement and our lead product candidate AFM13 is to our knowledge, the most advanced NK-cell engager in clinical development.

We also have a well-differentiated T-cell based approach, which includes our clinical candidate AFM11 and well provide an update on these clinical programs as well as our pre-clinical programs today. We employ about 75 full time equivalents with our headquarter located in Heidelberg, Germany, and affiliate offices in the U.S., that is Affimed Inc., as well as our subsidiary AbCheck in Plze, in the Czech Republic.

Slide 4. We have an unencumbered clinical and pre-clinical pipeline of NK and T-cell engagers, with our NK-cell engagers being developed in hematological diseases and solid tumors. Based on our NK-cell platform, we have one clinical and two pre-clinical programs in developments. And based on our T-cell platform, we have one program in our own clinical development. And second T-cell engager program based on our platform called AMV564 is being developed by Amphivena, a company of which we own about 18.5% fully diluted. AMV564 has recently entered clinical development.

Slide 5 summarizes our second quarter updates for our NK cell engager program. For AFM13, we have completed the dose escalation part of our Phase 1b combination study with Mercks Keytruda in Hodgkin Lymphoma and initiated the expansion phase. The AFM13 Phase 2a monotherapy trial in Hodgkin Lymphoma sponsored by the German Hodgkin Study Group is open to recruit under new study design, which includes patients pre-treated with both brentuximab vedotin and anti-PD1.

Columbia University has recently initiated a translational study of AFM13 in CD30-positive lymphoma with cutaneous manifestation and I will provide more detail later. We made further progress in our collaboration with MD Anderson Cancer Center to evaluate AFM13 in combination with MD Andersons NK cell product. In June, we presented new data for our NK cell engagers AFM24 and AFM26 at two conferences and I will go into detail later on this.

Slide 6 summarizes the progress, we have made with our T-cell engager. Two Phase 1 dose-escalation studies are ongoing with AFM11, which offer a significant opportunity to address the high unmet medical need in diffuse large B-Cell lymphoma and mantle cell lymphoma. We believe that both the properties of AFM11 and the design of our studies can attract, specifically, mutations of other drugs in development.

Both dose escalation studies, which are conducted in ALL and in NHL respectively are designed with accelerated titration followed by a classical 3+3 design. In both studies, AFM11 was overall well tolerated with no dose limits and toxicity observed to date. In the AFM11 study in relapsed refractory ALL, which was initiated in September 2016, patients are currently being recruited into the fourth dose cohort. 12 sites are open and recruiting in the Czech Republic, Poland, Russia, Austria and Israel.

As mentioned, no DLTs were observed in particular no AFM11 related grade 3 or grade 4 neurotoxicity or side effects are frequently observed with T-cell engaging antibody agents observed. In our study of AFM11 in relapsed refractory NHL, patients are currently being recruited into the third dose cohort. Recall that this study has been amended in the past to enroll patients under a new revised study design.

We believe that we have addressed this lower than effective recruitment by opening further trial sites. A total of 10 sites are now opened in the Czech Republic, Poland, Germany as well as the U.S. Like in our ALL trial, no AFM11 related grade 3 or grade 4 neurotoxicity was observed to date under their revised study design. We intend to provide regular update on both the AFM11 studies in the future.

A second T-cell engager program based on our platform is AMV564, a bispecific tetravalent CD33/CD3 antibody developed by Amphivena in AML. A Phase 1 study is recruiting. However, no further updates have been provided by Amphivena.

Slide 7 shows our platform, which is very distinguished from others as, in contrast, the most comparatives were developing tetravalent bispecific molecules. The bivalent binding of two receptors on two different cells enables high-affinity binding through the avidity effect, which is advantageous to maintain high specificity at very high affinity.

We believe that this is very important in order to obtain a favorable safety profile. Furthermore, our platform allows multi-specificity in the tailored PK. Further differentiating Affimed, while most immune cell engaging approaches to date focus on T cells, our technology platform reliably generates both T and NK-cell engagers.

While increasingly NK-cells are becoming a cornerstone of cancer immunotherapy, and we’re excited to be pioneering this development. There are a number of reasons why NK-cell-based approaches are very attractive and one of the reasons is that there seems to be a positive correlation between NK-cell infiltration and clinical outcome in patients.

In this context, it has been described that a low cytotoxicity is associated with higher incidence of cancer. In addition, recent clinical data show improved anti-tumor responses of ex vivo expanded and activated NK-cell populations. NK-cell-based immunotherapy has recently advanced with different treatment approaches, including engagers, check points, cytokines and adoptive cellular transfer.

To-date, it seems that NK-cell-based approaches have this strong advantage of controlling a well manageable favorable safety profile. This creates an opportunity for NK-cell redirection to address the lack of recognition of cancer cells and also allows for potential combination of NK-cells with other approaches to enhance efficacy.

A common theme in all different cancer types is the ability of the tumor cell to evade recognition by the immune system and, specifically, by NK-cells as shown on Slide 9. Normally, NK-cells are capable of killing foreign or aberrant cells, like tumor cells, have acquired mechanisms to escape the so-called immune surveillance.

As a result, such NK-cells cannot recognize tumor cells as foreign or aberrant and, therefore, cannot fight them. We believe that our platform has the potential to overcome these limitations by disabling the tumor evasion mechanisms, and I will explain on the next slide what this belief is based on.

Our expertise and leadership in natural-killer cell-based approaches is one of our key assets. As we can see here, there are a multitude of activating and inhibitory NK-cell receptors being discovered that CD16A, a dominant activating receptor on innate immune cells, is the only activating receptor that triggers the cytotoxic activity of nave human NK cells, even in the absence of costimulatory signals.

Based on these properties and on our preclinical and clinical data generated to date, we believe that targeting CD16A is key for efficient recruitment of and killing by NK cells and macrophages. We have secured a solid IP position around CD16A targets.

Slide 10. We believe that through targeting CD16A with high affinity and specificity, the significant limitations of IgGs can differ. With our tetravalent bispecific immune cell engagers, we can restore NK-cell killing in tumor immune control, and this is depicted here.

Let me explain in more detail why we believe that our approach is superior compared to IgG-based approaches. The human body is not using NK-cell engagement by IgG to eliminate cancer cells. However, this mechanism is used for cells infected by viruses or bacteria.

In this situation, the human immune system generates a collagen antibody response that highly decorates such infected cells or organisms.

Highly decorated means that many different proteins are expressed on the cell surface, which can then be found bound by antibodies. This polyclonal and high-density binding leads to NK-cells killing upon high avidity XP binding, plus antibodies for CD16A on the NK-cell and other XP gamma receptors, for example, CD32 and CD64.

In the setting of targetable cancer cells, however, with IgG, the situation is very different. Firstly, the therapeutic molecule targets a single epitope. Hence, it confers ammonia killing response. And secondly, there are cancer cells which express only very low numbers of the desired target.

The consequence of this very low target density is an insufficient amount of IgG, decorating the cancer cells and thereby not being able to efficiently recruit immune cells. This is shown in the middle picture. Interesting, most therapeutic monoclonal antibodies are target-modulating antibodies, such as cetuximab, polatuzumab, gevokizumab, just to mention a few of them.

We are addressing this limitation by targeting CD16A with high affinity and specificity, as shown. Indeed, our immune cell engagers has the potential to elicit a robust NK-cell killing and immune control due to multivalent and apparent high-affinity binding to CD16A even at limiting antigen densities on the target.

Slide 11, furthermore, CD16A in confers additional superior engager features. The binding of immune cells through CD16A with high affinity and specificity induces NK-cell activation, which triggers an integrated immune response that can be mediated by both innate and adaptive immune cells. In particular, our NK-cell engagers do not bind to CD16B and neutrophils, which avoids the sync effect. Their affinity has been demonstrated to be over 1,000 fold higher than that of monoclonal antibodies and our engagers bind independently of the 158 valine phenylalanine polymorphism.

Most importantly, theres virtually no competition with plasma IgG, which is shown here. In the ground stage, CD16A on innate immune cells is occupied by polyclonal plasma IgG. But there is a huge excess of plasma IgG versus therapeutic antibodies, this creates a significant threshold for FC-based therapeutic antibodies, however, not for CD16A target enhancement.

Our tetravalent and bispecific molecules, which recognize a different epitope from CD16A, are virtually unaffected by plasma IgG. All these unique features result in overall increased potency and efficacy of NK-cell engagers.

Slide 12. Our lead candidate, CD30/CD16A-specific NK-cell engager, AFM13 is a first-in-class antibody suitable for mono and combination therapy. This has demonstrated safety and clinical activity in heavily pretreated Hodgkin lymphoma patients in a Phase 1 study. In this Phase 1 study, tumor shrinkage and potential responses were observed in patients treated with four weekly doses of at least 1.5 mg/kg of AFM13. In 62% of patients, which was eight out of thirteen patients, we observed tumor shrinkage in 23% of patients, which was a total of three out of thirteen experienced partial response. None of the patients experiencing a PR had been previously treated with brentuximab vedotin.

Recall, that in our investigation the Phase 2a trial for AFM13 in relapsed and refractory Hodgkin lymphoma, which is led by the German Hodgkin Study Group, we have previously guided to change the study protocol to ensure a recruitment of a homogeneous patient population pre-treated with both BV and anti-PD1 antibodies. The study is now open to recruit under the new study design.

We had also provided some preliminary data from patients enrolled under the original study protocol, where partial responses were observed in two of seven evaluated patients who had been pre-treated with brentuximab vedotin, but were anti-PD1 naive. This suggests, now, for the first time that AFM13 is active as a single agent in this heavily pre-treated group of patients and, in particular, that AFM13 is active post brentuximab vedotin. We have learned from the study sponsor that both after-responders had failed BV as the most recent treatment prior to AFM13 therapy, with one patient experiencing stable disease and the other one partial in the progressive disease under the BV treatment.

As previously guided, full data from the ongoing study will be presented upon its anticipated completion in 2019. And prior to that, a decision of data publication time points will be made together with the German Hodgkin Study Group.

We are further developing AFM13 as a combination therapy. Preclinical affinity has been demonstrated in combination with anti-PD1 in vivo in a PDX model. This has been the basis of our Phase 1b trial in relapsed refractory Hodgkin lymphoma in combination with Mercks Keytruda. And here, we have completed the dose escalation part of the trial. In detail, three patients were enrolled into dose levels one and two, respectively, and six patients were enrolled into dose level three. While no grade three or four adverse events related to the study treatment were observed, one DLT was observed in cohort 3, which was a repeated grade two infusion-related reaction, leading to discontinuation of AFM13 treatment. This event is classified as a DLT according to the protocol definition. No further DLTs occurred.

The dose expansion cohort has been initiated with the highest dose explored during dose escalation. Data readout is ongoing in the treated cohort and we intend to present data from the dose escalation at a scientific medical conference in the second half of 2017.

Another update this quarter is that Columbia University has initiated a translational Phase 1b/2a study to evaluate the validity of activity of AFM13 in patients with relapsed and refractory CD30-positive lymphoma with cutaneous manifestation. Affirmed is supporting this trial which is designed to allow for serial biopsies, thereby enabling assessment of NK-cell biology and tumor cell killing within the tumor environment. The first patient was enrolled into the study in July 2017. In general, we view CD30-positive lymphoma as an attractive indication that may broaden the potential of AFM13. In terms of further guidance, we will work together with Columbia University to provide update on this study.

Slide 13. Additional opportunities for our NK-cell engagers include combinations with adoptive NK-cell transfer. Patients on NK cells can be stimulated by monotherapy using NK-cell engagers to overcome tumor immune evasion and immunosuppression. Ex vivo expansion and stimulation of autologous NK-cells followed by reinfusion alone or in combination with NK cell engager, is a viable therapeutic approach providing increased numbers of activated NK cells. Alternatively, NK cells can be derived from peripheral blood, cord blood or IPS cells from healthy donors, which is an allogeneic setting, or from immortalized cells. After ex vivo stimulation and expansion, the NK cells are infused into the patients in combination with NK cell engagers.

We are investigating this approach with our partner MD Anderson. Initially, we plan to investigate AFM13 with MDACCs NK-cell product in the transplant setting. Preclinical research activities are on track and these are intended to be followed by Phase 1 clinical trial. Proof-of-concept for this combination would also pave the way for combinations of other pipeline product such as for AFM23.

Affimed holds an option to exclusive worldwide rights to develop and commercialize any product developed under the collaboration. In addition to our clinical product candidates, we have created a strong preclinical pipeline. Over the last quarter we have further characterized our most advanced preclinical candidates, AFM24 and AFM26, which we are developing for three solid tumors and multiple myeloma respectively.

Despite several marketed agents such as cetuximab and tyrosine kinase inhibitor or TKIs, there is a significant medical need for a novel approach to treat EGF receptor-positive tumor. Both efficacy and toxicity can be addressed. EGFR-blocking drugs have been described to have side-effects including serious skin toxicity which might impact physicians willingness to prescribe a drug. In terms of efficacy, there is a need to overcome intrinsic or acquired resistance. For example, there is no clear indication of efficacy of EGFR-blocking antibodies in patients with RAS mutation.

We are developing a first-in-class NK cell engager designed to overcome the limitations of conventional therapy. AFM24 is designed to effectively treat EGFR-expressing solid tumors, such as lung and neck, or colon cancers. It is an EGFR/CD16A targeting tetravalent bispecific antibody that is well differentiated from cetuximab, it is more potent cytotoxicity in vitro and in vivo including a potential to kill RAS-mutant cell lines. There is novel mechanism of action in safety profile and it has the potential to overcome intrinsic or acquired resistance, which is described by many patients with EGFR positive tumors.

AFM24s potent NK cell recruitment may enable the shift of the validated target EGF receptor, primary receptor block toward immuno-oncology. We have identified several development candidates for which we have initiated IND-enabling studies.

Slide 15, there are several factors which differentiate AFM24 from other therapy. Firstly, AFM24 is differentiated through its efficacy. Here you can see that in vitro, our NK cell engager which is highly potent tumor cell killing independent of RAS mutational status. In vivo, we have demonstrated efficacy in tumors resistant to EGFR targeting agents. Importantly, as shown in the graphs on the right hand side, AFM24 was similarly efficacious in a cetuximab-sensitive model.

Secondly, AFM24 is differentiated through safety, Slide 16. We have completed pilot toxicity studies in cynomolgus monkeys with no major safety findings. At the EACR-AACR-SIC Special Conference, we presented data on a dose-range binder study in which AFM24 was dosed up to 93.75 mg/kg and a repeated dose study in which AFM24 was dosed up to 30 mg/kg in 4 weeks.

No AFM24-related macro or microscopic changes were seen in tissues including vital organs, skin and injection site. Importantly, there was no evidence of skin toxicity in those studies. Also no signs of delayed toxicity was observed in the repeated dose study recovery animals. On a molecular level, we learned from in vitro toxicology studies but there was no cytokine release or NK cell proliferation in the absence of target cells. This further substantiates AFM24s potential beneficial safety profile.

Slide 17, like for EGFR targeted tumors, there is a significant need for a novel approach to treat multiple myeloma. Even though, new therapies have significant improved outcomes, cure still remains elusive and the medical need to achieve minimal residual disease negativity is not yet addressed.

MRD positivity is associated with a poorer prognosis, and it has been recorded that persistent MRD by predictive marker of unsustained complete response. A particular hurdle for therapeutics aimed at immune cell engagement are very high M-protein serum levels up to 170mg/mL. Indeed the competition by serum IgG is known to strongly impair antibody-dependent cell-mediated cytotoxicity, the activity of monoclonal antibodies.

We are developing AFM26 to overcome the limitations of conventional therapies in multiple myeloma. AFM26 is a first-in-class tetravalent bispecific antibody targeting BCMA/CD16A. Targeting BCMA and employing NK cell engagement offers the potential to achieve MRD-negativity. For AFM26, NK cell binding is largely unaffected by circulating IgG, which creates the potential of NK cell activation in the presence of M-protein.

Indeed, the high affinity binding to both target and NK cells leads to a prolonged cell retention. This is shown on the right on the slide on the right bottom. AFM26 shows high cytotoxicity cytotoxic activity towards both low and high BCMA-expressing myeloma cells. AFM26 may be potentially safer than T cell-based approaches, which would allow for faster development timelines. Based on these characteristics, AFM26 might be positioned in first line of combination with adoptive NK-cell transfer during ASCT or in a salvage setting.

AFM26 binds the B-cell maturation antigen, which is an antigen ubiquitously expressed on malignant plasma cells. Its expression on healthy tissues is limited to plasma cells and peripheral dendritic cells. We believe the BCMA is an ideal target for immunotherapy of multiple myeloma.

At ASCO and at the EACR-AACR-SIC, both in June, well present the data on AFM26 NK-cell binding properties and activity. As shown here, these data underscore that compared to native and FC-enhanced IgG. AFM26 shows improved binding and cell surface retention.

Slide 20, we also show that AFM26 is well differentiated through target cell binding in potent NK-cell mediated tumor cell lysis. And this is shown here in comparison with two marketed agents, daratumumab and anti-CD38 antibody and elotuzumab, which targets PS1. Importantly, other than described for daratumumab and elotuzumab, AFM26 did not induce NK-cell mutation.

Slide 21, like our other NK-cell engagers, AFM26 is also well differentiated for other agents [indiscernible] safety. Here you can see that compared to a T-cell engager, AFM26 is similarly potent that shows a reduced cytokine release pattern. This point is going to improve safety profile, making AFM26 uniquely suited to engage NK-cells with multiple myeloma.

I will now hand over the call to our CFO, Florian Fischer, who will provide further details on the financial figures.

Florian Fischer

Thank you, Adi. Affimeds consolidated financial statements have been prepared in accordance with IFRS as issued by the International Accounting Standards Board or IASB. The consolidated financial statements are presented in euro, which is the companys functional and presentation currency. Therefore, all financial numbers that I will present here in this call unless otherwise noted will be in euros. Any numbers referring to Q2 2017 and Q2 2016 are unaudited.

Cash and cash equivalents and financial assets totaled 48.9 million as of June 2017 compared to 44.9 million as of December 31, 2016. The increase was primarily attributable to the net proceeds of 16.4 million from a public offering of common shares in the first quarter, and of 2.5 million from the drawdown of the second tranche of the loan from Silicon Valley Bank, largely offset by operational expenses.

Net cash used in operating activities was 13.1 million for the six months ended June 30, 2017compared to 17 million for the six months ended June 30, 2016. The decrease was primarily related to lower cash expenditure for research and development in connection with Affimeds development and collaboration programs and to the expiration of the Amphivena collaboration.

Affimed expects to have cash to fund our operations at least until the end of 2018. This provides runway for the planned development of our clinical programs, as well as for product discovery and early development activity.

Revenue for the second quarter of 2017 was 0.5 million compared to 2.1 million for the second quarter 2016. Revenue in the 2017 period was primarily derived from AbCheck services, while revenue in 2016 period predominantly to Affimeds collaboration with Amphivena.

R&D expenses for the second quarter of 2017 were 5.4 million compared to 8.6 million for the second quarter of 2016. The decrease was primarily related to lower expenses for AFM13 and our discovery and early stage development activities and the expiration of the Amphivena collaboration.

G&A expenses for the second quarter of 2017 were unchanged at 2.0 million compared to the second quarter of 2016. Net loss for the second quarter of 2017 was 7.9 million, or 0.18 per common share, compared to a net loss of 8 million or 0.24 per common share for the second quarter of 2016.

The decrease of operating expenses was offset by lower revenue. In addition, the result was affected by finance costs of 1.2 million in the second quarter of 2017, whereas finance income of 0.5 million was shown in the second quarter of 2016.

I will now turn the call back over to Adi for a summary of our two clinical programs and our pipeline. Adi?

Adi Hoess

Thanks a lot Florian. Our strategy is to maximize the value of our unencumbered clinical and preclinical pipeline of NK-cell and T-cell engagers, as well as from our platform. Were leveraging our lead product, AFM13, for CD30-positive lymphoma initially focusing on the Hodgkin Lymphoma salvage setting enabling a fast development path and allowing the establishment of a cost efficient marketing and sales structure.

In addition, we believe investigating AFM13, both as monotherapy and in combination with Keytruda, reduces its development. Overall, our preclinical and clinical strategy is designed from the scientific leadership of our NK-cell platform with CD16A as proprietary target. We are expanding the preclinical and clinical activities of our tetravalent and bispecific NK-cell engager platform in solid tumors with our preclinical candidate AFM24 and in hematologic diseases, where we intend to leverage additional opportunities for AFM13 and AFM26, for example, in combination with adoptive NK-cells. We also develop T-cell engagers and our lead T-cell engager, AFM11, is being investigated in two ongoing ALL and NHL trials. BMV564, a T-cell engager derived from our technology platform, is in clinical development through Amphivena to treat AML.

In addition, as mentioned earlier, moving beyond our standard format, we are developing different tetravalent bispecific antibody formats tailored to specific indications and patient populations. And as outlined in previous earnings calls, we have more projects ongoing at the discovery stage and preclinically, including molecules developed from our MHD type complex targeting platform.

Thank you very much for your interest. The call is now open for questions.

Question-and-Answer Session

Operator

Thank you. [Operator Instructions] Our first question now comes from Maury Raycroft from Jefferies. Please go ahead.

Maury Raycroft

Good morning. Thanks for taking my questions. So I was wondering if you can mention what the AFM13 dose was that the DLT patient received in the combo trial? And then what youre going to use in the expansion cohort? And then is this dose higher, lower or in line with your predictions?

Adi Hoess

Hi, Maury, this is Adi. What we have done is we have used or given a PD-1 as its active dose and have dosed up AFM13 under the following strategy, under the following regime. We always are initially giving AFM13 three times per week for two weeks. Then, we give AFM13 once weekly for six weeks and, subsequently, we dose AFM13 every three weeks. The starting dose was 0.15 mg/kg and then switching to 0.5 mg/kg, the next one was 0.5 mg/kg going to 1.5 mg/kg, and the highest dose was 3 mg/kg going then to 7 mg/kg. So the three is always three times per week, and the seven is the weekly or every three weeks. We have seen 1 DLT in the highest dose. So at three times 3 mg/kg and once 7 mg/kg then have included an additional three patients and have not observed another DLT. So thats why we decided to go with the highest dose of 3 mg/kg three times per week subsequently given and then subsequently followed by 7 mg/kg.

Maury Raycroft

Got it, okay. And you also mentioned earlier about the two PRs generated with the monotherapy treatment? And I think you said there is a stable disease, but I missed some of the additional context, and I was just wondering if you can recap that for me?

Adi Hoess

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Affimed Therapeutics’ (AFMD) CEO Adi Hoess on Q2 2017 Results – Earnings Call Transcript – Seeking Alpha

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