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Goal is vaccine that targets inflammation in joints

Using CRISPR technology, a team of researchers led by Farshid Guilak, PhD, at Washington University School of Medicine in St. Louis, rewired stem cells' genetic circuits to produce an anti-inflammatory arthritis drug when the cells encounter inflammation. The technique eventually could act as a vaccine for arthritis and other chronic conditions.

Using new gene-editing technology, researchers have rewired mouse stem cells to fight inflammation caused by arthritis and other chronic conditions. Such stem cells, known as SMART cells (Stem cells Modified for Autonomous Regenerative Therapy),develop into cartilage cells that produce a biologic anti-inflammatory drug that, ideally, will replace arthritic cartilage and simultaneously protect joints and other tissues from damage that occurs with chronic inflammation.

The cells were developed at Washington University School of Medicine in St. Louis and Shriners Hospitals for Children-St. Louis, in collaboration with investigators at Duke University and Cytex Therapeutics Inc., both in Durham, N.C. The researchers initially worked with skin cells taken from the tails of mice and converted those cells into stem cells. Then, using the gene-editing tool CRISPR in cells grown in culture, they removed a key gene in the inflammatory process and replaced it with a gene that releases a biologic drug that combats inflammation.

The research is availableonline April 27 in the journal Stem Cell Reports.

Our goal is to package the rewired stem cells as a vaccine for arthritis, which would deliver an anti-inflammatory drug to an arthritic joint but only when it is needed, said Farshid Guilak, PhD, the papers senior author and a professor of orthopedic surgery at Washington University School of Medicine. To do this, we needed to create a smart cell.

Many current drugs used to treat arthritis including Enbrel, Humira and Remicade attack an inflammation-promoting molecule called tumor necrosis factor-alpha (TNF-alpha). But the problem with these drugs is that they are given systemically rather than targeted to joints. As a result, they interfere with the immune system throughout the body and can make patients susceptible to side effects such as infections.

We want to use our gene-editing technology as a way to deliver targeted therapy in response to localized inflammation in a joint, as opposed to current drug therapies that can interfere with the inflammatory response through the entire body, said Guilak, also a professor of developmental biology and of biomedical engineering and co-director of Washington Universitys Center of Regenerative Medicine. If this strategy proves to be successful, the engineered cells only would block inflammation when inflammatory signals are released, such as during an arthritic flare in that joint.

As part of the study, Guilak and his colleagues grew mouse stem cells in a test tube and then used CRISPR technology to replace a critical mediator of inflammation with a TNF-alpha inhibitor.

Exploiting tools from synthetic biology, we found we could re-code the program that stem cells use to orchestrate their response to inflammation, said Jonathan Brunger, PhD, the papers first author and a postdoctoral fellow in cellular and molecular pharmacology at the University of California, San Francisco.

Over the course of a few days, the team directed the modified stem cells to grow into cartilage cells and produce cartilage tissue. Further experiments by the team showed that the engineered cartilage was protected from inflammation.

We hijacked an inflammatory pathway to create cells that produced a protective drug, Brunger said.

The researchers also encoded the stem/cartilage cells with genes that made the cells light up when responding to inflammation, so the scientists easily could determine when the cells were responding. Recently, Guilaks team has begun testing the engineered stem cells in mouse models of rheumatoid arthritis and other inflammatory diseases.

If the work can be replicated in animals and then developed into a clinical therapy, the engineered cells or cartilage grown from stem cells would respond to inflammation by releasing a biologic drug the TNF-alpha inhibitor that would protect the synthetic cartilage cells that Guilaks team created and the natural cartilage cells in specific joints.

When these cells see TNF-alpha, they rapidly activate a therapy that reduces inflammation, Guilak explained. We believe this strategy also may work for other systems that depend on a feedback loop. In diabetes, for example, its possible we could make stem cells that would sense glucose and turn on insulin in response. We are using pluripotent stem cells, so we can make them into any cell type, and with CRISPR, we can remove or insert genes that have the potential to treat many types of disorders.

With an eye toward further applications of this approach, Brunger added, The ability to build living tissues from smart stem cells that precisely respond to their environment opens up exciting possibilities for investigation in regenerative medicine.

Brunger JM, Zutshi A, Willard VP, Gersbach CA, Guilak F. Genome engineering of stem cells for autonomously regulated, closed-loop delivery of biologic drugs. Stem Cell Reports. April 27, 2017.

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging of the National Institutes of Health (NIH), grant numbers AR061042, AR50245, AR46652, AR48182, AR067467, AR065956, AG15768, OD008586. Additional funding provided by the Nancy Taylor Foundation for Chronic Diseases; the Arthritis Foundation; the National Science Foundation (NSF), CAREER award number CBET-1151035; and the Collaborative Research Center of the AO Foundation, Davos, Switzerland.

Authors Farshid Guilak, and Vincent Willard have a financial interest in Cytex Therapeutics of Durham, N.C., which may choose to license this technology. Cytex is a startup founded by some of the investigators. They could realize financial gain if the technology eventually is approved for clinical use.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Global CAR T Cell Therapy Market & Clinical Trials Insight 2022: Pipeline Analysis by Company, Indication & Phase … – PR Newswire (press…

The report highlights the ongoing clinical and non-clinical advancement in the field of Car T Cell Therapy. As per report findings, the promise of CAR modified T cell therapy derives from its combined immunologic benefits and include the specificity of a targeted antibody, the ability to expand the T cell population and the potential for long term persistence to facilitate the ongoing tumor surveillance. The success in early phase trials, assess the feasibility of evaluating the treatment modality across the multiple centers and in larger patients. Currently, there are 99 CAR T Cell based therapies in clinical pipeline and most of them belong to Phase-I and Phase-I/II clinical trials.

In recent years, researchers have identified the chimeric antigen receptor as a potential target for molecular genetics to insert a new epitopes on the receptor region which allows a degree of control of the immune system. CAR T cell therapy satisfy the need to explore new and efficacious adoptive T cell therapy. The gene transfer technology could efficiently introduce the genes encoding CARs into the immune effector cells. The transferring of engineered T cells provides the specific antigen binding in a non-major histocompatibility complex. The promise of CAR modified T cell therapy derives from its combined immunologic benefits and include the specificity of a targeted antibody, the ability to expand the T cell population and the potential for long term persistence to facilitate the ongoing tumor surveillance. The success in early phase trials, assess the feasibility of evaluating the treatment modality across the multiple centers and in larger patients.

Companies Mentioned

Key Topics Covered:

1. Chimeric Antigen Receptor (CAR) T Cell Therapy - Next Era in Immuno Oncology

2. Evolution of Chimeric Antigen Receptor (CAR) T-Cell Design

3. Principle of Chimeric Antigen Receptor Design

4. CAR T Cell Therapies Delivery Pipeline & Mechanism of Action

5. Approaches to Improve the CAR T Cell Therapy

6. Global CAR T Cell Therapy Clinical Trials for Cancer Treatment

7. Global CAR T Cell Therapies Clinical Pipeline by Company, Indication & Phase

8. Global Market Scenario of CAR T Cell Therapy

9. Global Market Size of CAR T Cell Therapy

10. Global CAR T Cell Therapy Market Dynamics

11. Global CAR T Cell Therapy Market Future Prospects

12. Competitive Landscape

For more information about this report visit http://www.researchandmarkets.com/research/q57z4j/global_car_t_cell

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Laura Wood, Senior Manager press@researchandmarkets.com

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Banking Teeth for Stem Cell Therapy – HealthCentral.com

Banking Teeth for Stem Cell Therapy

Banking baby teeth or wisdom teetha practice thats been around for about 10 yearsis becoming more widely accepted in developed areas of the world, according to researchers. It involves cryopreserving teethand the dental stem cells they containfor potential stem cell therapy in the future.

Most research surrounding dental stem cells and tooth banking is still in the experimental stage and, at this time, scientists disagree about whether its worthwhileunlike cord blood banking, which has proven benefits for stem cell therapy. Some research suggests preserved dental stem cells could one day be used to regenerate healthy tissue and help fight complex diseases. But many experts remain less convinced of the potential benefits, as so much of the research is preliminary.

So far, the research has centered around dentinthe innermost hard layer of the tooth, below the enameland soft tissue beneath the dentin called pulp. The pulp contains the tooths nerve and blood supplies. In studying how teeth repair themselvesfrom a cavity, for exampleresearchers discovered that teeth contain stem cells. More studies are needed to determine if these dental stem cells can be harvested, preserved, stored, and someday used for stem cell therapy.

Image Credit: iStock

Sourced from: CNN

A new study suggests that cardiovascular decompensationa life-threatening drop in blood pressure caused by serious injuries involving significant blood lossmay be treated temporarily at the scene or during transport to the hospital simply by applying a bag of ice water to the injured persons face. Decompensation, which remains a dangerous complication even after bleeding has stopped, reduces the delivery of oxygen to the brain, heart, and other vital organs.

For the study, ten healthy volunteers were placed in a special chamber that simulates blood circulation after a person has lost one-half to one liter of blood and a tourniquet has been applied to stop the bleeding. Researchers applied bags of ice water or bags of room-temperature water to the study participants faces for 15 minutes while they continuously monitored cardiovascular function. They discovered that participants treated with bags of ice water experienced significant increases in blood pressure, suggesting that applying ice water can improve cardiovascular function after blood loss and prevent a dangerous drop in blood pressure.

Researchers expect to begin clinical trials soon. The hope is that this simple technique can be used by first responders or medics in the field of combat to improve survival rates after injuries involving blood loss by providing extra time for transport to a hospital or other medical facility.

Image Credit: iStock

Sourced from: ScienceDaily

Cooking dinner at homerather than eating outis a good way to eat healthier and save money, according to researchers at Oregon State University and the University of Washington. Historically, people with a higher socioeconomic status are generally healthier than those with lower incomes, but this study suggests otherwiseIF more money means dining out more often and less money means eating at home.

The study involved about 400 adults in the Seattle-area. Study participants were surveyed about their cooking and eating behaviors for one week and provided various socioeconomic information. Their weekly food intake was graded using the Healthy Eating Index (HEI)a scale that ranges from 0 to 100, with higher scores indicating a healthier diet.

According to researchers, cooking at home three times per week produced an average score of about 67 on the Healthy Eating Index, and cooking at home six times per week resulted in an average score of 74. Results of the study suggest that home-cooked dinners are associated with a diet lower in calories, sugar and fat, overall than dining out regularly.

Image Credit: iStock

Sourced from: Oregon State University

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Capricor Therapeutics to Present at the Alliance for Regenerative Medicine’s Cell & Gene Therapy Investor Day – Yahoo Finance

LOS ANGELES, April 26, 2017 /PRNewswire/ --Capricor Therapeutics, Inc. (CAPR), a clinical-stage biotechnology company developing first-in-class biological therapies for cardiac and other medical conditions, today announced that Linda Marbn, Ph.D., president and chief executive officer, is scheduled to present at the Alliance for Regenerative Medicine's 5th Annual Cell & Gene Therapy Investor Day on April 27, 2017 at The State Room in Boston, Massachusetts. The presentation will begin at approximately 9:40 a.m. eastern time and a live webcast of the event will be available at http://www.arminvestorday.com/webcast/.

About Capricor Therapeutics

Capricor Therapeutics, Inc. (CAPR) is a clinical-stage biotechnology company developing first-in-class biological therapies for cardiac and other medical conditions. Capricor's lead candidate, CAP-1002, is a cell-based candidate currently in clinical development for the treatment of Duchenne muscular dystrophy, myocardial infarction (heart attack), and heart failure. Capricor is exploring the potential of CAP-2003, a cell-free, exosome-based candidate, to treat a variety of disorders. For more information, visit http://www.capricor.com.

Cautionary Note Regarding Forward-Looking Statements

Statements in this press release regarding the efficacy, safety, and intended utilization of Capricor's product candidates; the initiation, conduct, size, timing and results of discovery efforts and clinical trials; the pace of enrollment of clinical trials; plans regarding regulatory filings, future research and clinical trials; plans regarding current and future collaborative activities and the ownership of commercial rights; scope, duration, validity and enforceability of intellectual property rights; future royalty streams, expectations with respect to the expected use of proceeds from the recently completed offerings and the anticipated effects of the offerings, and any other statements about Capricor's management team's future expectations, beliefs, goals, plans or prospects constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements that are not statements of historical fact (including statements containing the words "believes," "plans," "could," "anticipates," "expects," "estimates," "should," "target," "will," "would" and similar expressions) should also be considered to be forward-looking statements. There are a number of important factors that could cause actual results or events to differ materially from those indicated by such forward-looking statements. More information about these and other risks that may impact Capricor's business is set forth in Capricor's Annual Report on Form 10-K for the year ended December 31, 2016, as filed with the Securities and Exchange Commission on March 16, 2017, and in its Registration Statement on Form S-3, as filed with the Securities and Exchange Commission on September 28, 2015, together with prospectus supplements thereto. All forward-looking statements in this press release are based on information available to Capricor as of the date hereof, and Capricor assumes no obligation to update these forward-looking statements.

CAP-1002 is an Investigational New Drug and is not approved for any indications. Capricor's exosomes technology, including CAP-2003, has not yet been approved for clinical investigation.

For more information, please contact:

Corporate Capricor Therapeutics, Inc. AJ Bergmann, Vice President of Finance +1-310-358-3200 abergmann@capricor.com

Investor RelationsArgot Partners Kimberly Minarovich +1-212-600-1902 kimberly@argotpartners.com

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Capricor Therapeutics to Present at the Alliance for Regenerative Medicine's Cell & Gene Therapy Investor Day - Yahoo Finance

Stem cell lines grown in lab dish may acquire mutations | Harvard … – Harvard Gazette

Photo by Hannah Robbins/HSCI

In a cross-school collaboration, Harvard researchers Steve McCarroll (left) and Kevin Eggan couple stem cell science with genetics and genomicsto advance the understanding of human brain illnesses. Their latest project identifiedmutations that stem cell lines acquire in culture.

Regenerative medicine using human pluripotent stem cells to grow transplantable tissue outside the body carries the promise to treat a range of intractable disorders, such as diabetes and Parkinsons disease.

However, a research team from the Harvard Stem Cell Institute (HSCI), Harvard Medical School (HMS), and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard has found that as stem cell lines grow in a lab dish, they often acquire mutations in the TP53 (p53) gene, an important tumor suppressor responsible for controlling cell growth and division.

Their research suggests that genetic sequencing technologies should be used to screen for mutated cells in stem cell cultures, so that cultures with mutated cells can be excluded from scientific experiments and clinical therapies. If such methods are not employed it could lead to an elevated cancer risk in those receiving transplants.

The paper, published online today in the journal Nature, comes at just the right time, the researchers said, as experimental treatments using human pluripotent stem cells are ramping up across the country.

Our results underscore the need for the field of regenerative medicine to proceed with care, said the studys co-corresponding author Kevin Eggan, an HSCI principal faculty member and the director of stem cell biology for the Stanley Center. Eggans lab in Harvard Universitys Department of Stem Cell and Regenerative Biology uses human stem cells to study the mechanisms of brain disorders, including amyotrophic lateral sclerosis, intellectual disability, and schizophrenia.

The research, the team said, should not discourage the pursuit of experimental treatments but instead be heeded as a call to screen rigorously all cell lines for mutations at various stages of development as well as immediately before transplantation.

Our findings indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies, Eggan said. Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods.

With human stem cells, researchers can re-create human tissue in the lab. This enables them to study the mechanisms by which certain genes can predispose an individual to a particular disease. Eggan has been working with Steve McCarroll, associate professor of genetics at Harvard Medical School and director of genetics at the Stanley Center, to study how genes shape the biology of neurons, which can be derived from these stem cells.

McCarrolls lab recently discovered a common, precancerous condition in which a blood stem cell in the body acquires a pro-growth mutation and then outcompetes a persons normal stem cells, becoming the dominant generator of his or her blood cells. People in whom this condition has appeared are 12 times likelier to develop blood cancer later in life. The studys lead authors, Florian Merkle and Sulagna Ghosh, collaborated with Eggan and McCarroll to test whether laboratory-grown stem cells might be vulnerable to an analogous process.

Cells in the lab, like cells in the body, acquire mutations all the time, said McCarroll, co-corresponding author. Mutations in most genes have little impact on the larger tissue or cell line. But cells with a pro-growth mutation can outcompete other cells, become very numerous, and take over a tissue. We found that this process of clonal selection the basis of cancer formation in the body is also routinely happening in laboratories.

To find acquired mutations, the researchers performed genetic analyses on 140 stem cell lines 26 of which were developed for therapeutic purposes using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 were listed on the National Institutes of Health registry of human pluripotent stem cells.

While we expected to find some mutations in stem cell lines, we were surprised to find that about 5 percent of the stem cell lines we analyzed had acquired mutations in a tumor-suppressing gene called p53, said Merkle.

Nicknamed the guardian of the genome, p53 controls cell growth and cell death. People who inherit p53 mutations develop a rare disorder called Li-Fraumeni Syndrome, which confers a near 100 percent risk of developing cancer in a wide range of tissue types.

The specific mutations that the researchers observed are dominant-negative mutations, meaning that when they are present on even one copy of p53, they are able to compromise the function of the normal protein, whose components are made from both gene copies. The exact same dominant-negative mutations are among the most commonly observed mutations in human cancers.

These precise mutations are very familiar to cancer scientists. They are among the worst p53 mutations to have, said Ghosh, a co-lead author of the study.

The researchers performed a sophisticated set of DNA analyses to rule out the possibility that these mutations had been inherited rather than acquired as the cells grew in the lab. In subsequent experiments, the Harvard scientists found that p53 mutant cells outperformed and outcompeted non-mutant cells in the lab dish. In other words, a culture with a million healthy cells and one p53 mutant cell, said Eggan, could quickly become a culture of only mutant cells.

The spectrum of tissues at risk for transformation when harboring a p53 mutation includes many of those that we would like to target for repair with regenerative medicine using human pluripotent stem cells, said Eggan. Those organs include the pancreas, brain, blood, bone, skin, liver, and lungs.

However, Eggan and McCarroll emphasized that now that this phenomenon has been found, inexpensive gene-sequencing tests will allow researchers to identify and remove from the production line cell cultures with worrisome mutations that might prove dangerous after transplantation.

The researchers point out in their paper that screening approaches to identify these p53 mutations and others that confer cancer risk already exist and are used in cancer diagnostics. In fact, in an ongoing clinical trial that is transplanting cells derived from induced pluripotent stem cells, gene sequencing is used to ensure the transplanted cell products are free of dangerous mutations.

This work was supported by the Harvard Stem Cell Institute, the Stanley Center for Psychiatric Research, the Rosetrees Trust, the Azrieli Foundation, Howard Hughes Medical Institute, the Wellcome Trust, the Medical Research Council, the Academy of Medical Sciences, and by grants from the NIH.

By Al Powell, Harvard Staff Writer | April 26, 2017

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Stem cell lines grown in lab dish may acquire mutations | Harvard ... - Harvard Gazette

Neurological Regenerative Medicine Unlocking the Potential of … – SelectScience

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Dr. Murdoch is a stem cell biologist with an interest in development and regenerative medicine. After completing post-doctoral training at Yale University, she took the role of Assistant Professor at Eastern Connecticut State University, where her time is split between teaching and researching nervous system development.

As our understanding of stem cells has increased, the possibility of using stem cell therapies to treat disease is on the horizon. Barbara Murdoch, Ph.D., Assistant Professor at Eastern Connecticut State University, is studying stem cells found in the olfactory epithelium (OE) with the aim of finding therapies for neurodegeneration.

Exclusive neurogenic niche: The olfactory epithelium

The OE is one of the few tissues in the body which is known to regenerate neurons, preserving our sense of smell throughout our lives.

Have you ever had the experience where you smell something and the scent evokes a memory from years back in time? asked Dr. Murdoch. This is because not only can the stem cells in the OE divide and differentiate to replace the lost neurons, but they can also recreate the exact same connection in the brain as the neuron they are replacing.

Dr. Murdoch explained how by studying these stem cells, she hoped to elucidate the environment and signaling molecules which restrict them to certain cell fates. The aim of her research is to direct neural stem/progenitor cells to create neurons in vitro. We can transplant neuronal precursor cells which are on their way to make neurons into patients, for example to help them recover after a stroke, said Dr. Murdoch.

Development of the olfactory epithelium approaches

One approach to understanding what dictates cell fate is to investigate the regions enriched for progenitors and determine their local microenvironment. The communication signals forming the microenvironment can be used to drive the production of new neurons from neuronal precursors in vitro. To investigate olfactory development, Dr. Murdoch carries out confocal microscopy using antibodies against numerous cell markers such as nestin, 3-tubulin and GFAP.

I was at a meeting when, just by chance, I came across a representative from Covance (now BioLegend) who had an anti-nestin antibody and was kind enough to give me a sample. When I tried it, it was brilliant in the olfactory epithelium and the brain, said Dr. Murdoch.

Dr. Murdoch published her findings in the 2008 Journal of Neuroscience paper, demonstrating that there were stem cell-like cells in the embryonic OE which are very similar to neural cells in the brain known as radial glia cells. Radial glia are responsible for the production of most if not all neurons in the brain. Previously, it was thought that radial glia cells were restricted to the central nervous system, but Dr. Murdochs research shows that they are also present in the OE, which is part of the peripheral nervous system.

The reason I think this was missed by so many other researchers was that the antibody that was typically used as a marker of neural stem cells, the anti-nestin antibody, worked well in the brain but not very well in the OE, Dr. Murdoch explained. However, the new antibody from BioLegend was targeting a different epitope, allowing it to identify and bind well to nestin expressed in the OE.

Dr. Murdoch described finding effective primary antibodies as a somewhat hit or miss process. Often when Im searching for antibodies, I try to get a sample and test it with the organism and tissue type Im using. When you find antibodies that work, you stick with them. Thats the reason why I stick with the antibodies from BioLegend, as they are so specific time and time again, Dr. Murdoch added.

The image shows differentiation into neurons (green) and glia (red). Blue indicates cell nuclei. Provided by Dr. Murdoch.

Future research and application in regenerative medicine approaches

Now an Assistant Professor at Eastern Connecticut State University, Dr. Murdoch is furthering her research by using chick embryos as a model to study how the OE develops.

Were trying to find pockets of progenitor cells and learn what the environmental influences surrounding those cells are in vivo, Dr. Murdoch explained.

This research has implications for regenerative medicine, where the same signals found in vivo can be recreated in vitro to make new neurons from neural precursors, derived either from human embryonic or induced pluripotent stem cells. Future work will aim to construct 3D scaffolds combined with signaling molecules and matrices to affect cell fate, Dr. Murdoch said.

Research such as Dr. Murdochs is contributing to an improved understanding of the signaling cascades found in neurogenic niches. Understanding the factors which decide cell fate and coordinate the generation of complex tissue is an important step in developing stem cell therapies to treat neurodegenerative states, such as Parkinsons disease, traumatic brain injury and stroke.

Dr. Murdochs work is funded by the CSU-AAUP.

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