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 Parkinson's 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 in the journal Nature on April, 26, 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 study's co-corresponding author Kevin Eggan, an HSCI Principal Faculty member and the director of stem cell biology for the Stanley Center. Eggan's lab in Harvard University's 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 recreate 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.

McCarroll's 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 person's normal stem cells, becoming the dominant generator of his or her blood cells. People in whom this condition has appeared are 12 times more likely to develop blood cancer later in life. The study's 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 NIH registry of human pluripotent stem cells.

"While we expected to find some mutations in stem cell lines, we were surprised to find that about five 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, when 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 Sulagna 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 include 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 concerning 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 (iPSCs), gene sequencing is used to ensure the transplanted cell products are free of dangerous mutations.

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Genes need to be screened for stem cell transplants - Science Daily

Capricor Therapeutics, Inc. (NASDAQ: 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:

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To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/capricor-therapeutics-to-present-at-the-alliance-for-regenerative-medicines-cell--gene-therapy-investor-day-300445808.html

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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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Neurological Regenerative Medicine Unlocking the Potential of ... - SelectScience

Enlarge / Oh, there's that cure I was looking for.

Tried, true, and FDA-approved drugs for cancer and depressionalready in medicine cabinetsmay also be long-sought treatments for devastating brain diseases such as Alzheimers, Parkinsons, and other forms of dementia, according to a new study in Brain, a Journal of Neurology.

The research is still in early stages; it only involved mouse and cell experiments, which are frequently not predictive of how things will go in humans. Nevertheless, the preliminary findings are strong, and scientists are optimistic that the drugs couldone day help patients with progressive brain disease. Researchers are moving toward human trials. And this process would be streamlined because the drugs have already cleared safety tests. But even if the early findings hold up, it would still take years to reach patients.

In the preliminary tests, the two drugstrazodone hydrochloride, used to treat depression and anxiety, and dibenzoylmethane (DBM), effective against prostate and breast tumorscould shut down a devastating stress response in brain cells, known to be critical for the progression of brain diseases. The drugs both protected brain cells and restored memory in mice suffering from brain diseases.

"We're excited by the potential of these findings from this well-conducted and robust study, Doug Brown, of the Alzheimer's Society, told the BBC.

David Dexter, from Parkinson's UK, added that if these studies were replicated in human clinical trials, both trazodone and DBM could represent a major step forward.

For years, researchers have known that a stress response in cells, called unfolded protein response, or UPR, is involved in a bunch of neurodegenerative diseases. The response kicks in when theres a buildup of unfolded or misfolded proteins. Typically, protein chains are folded into specific 3D structures that are often critical for their function in the body. But this folding goes awry in some neurodegenerative conditions, such as prion diseases, Alzheimer's disease, Parkinson's disease, and other forms of dementia.

When this happens, UPR kicks in. It shuts down protein production, tries to junk the botched proteins, and gets protein production machinery back in order. If all goes well, the cell can resume normal protein production. But if it doesnt, UPR initiates apoptosis, aka cell suicide.

In neurodegenerative diseases, things dont go well; UPR is over-activated, and brain cells start dying off. Scientists know that hampering UPR can protect brain cells and restore memory in mice engineered to mimic having Alzheimer's disease. But so far, all the compounds found to knock back UPR were highly toxic or highly insoluble (they dont work as medicine).

For a drug discovery shortcut, researchers at the University of Cambridge wondered: do we already have drugs that can interfere with UPRbut just dont know it? They screened a library of 1,040 FDA-approved drugs to find out.

Because UPR is highly conserved across animals, the researchers could use worms to screen the drugs. They initially found 20 drugs that seemed to have UPR-dampening effects. Upon further testing, they whittled down the list to five, then to two.

In further cell experiments, both trazodone and DBM inhibited a specific step in UPR and restored protein production. In mice, the drugs traversed the blood-brain barrier. When the researchers infected mice with a prion disease, clinically relevant doses of either drug held back neurological symptoms, boosted survival, and substantially reduced loss of brain cells in most of the infected mice. In mice that modeled a type of dementia, called frontotemporal dementia, both drugs could rescue the rodents memory and restore protein synthesis in brain cells.

The two drugs were markedly neuroprotective, the authors conclude. These drugs therefore represent an important step forward in the pursuit of disease-modifying treatments for Alzheimers and related disorders.

Trazodone, the authors note, is even already approved for use in the elderly. Clinical trials are the next step.

Brain, 2017. DOI: 10.1093/brain/awx074 (About DOIs).

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Drugs already in medicine cabinets may fight dementia, early data suggests - Ars Technica

On Saturday evening I, along with millions of other people, watched the premiere of Auntie Oprahs film, The Immortal Life of Henrietta Lacks, on HBO. At the beginning of the film, I was nestled in my bed, eating a bowl of popcorn. I knew the premise of the movie and seriously, who doesnt love a good Oprah Winfrey performance (and let me just say, as usual, she delivered). But by the middle of the film, I was no longer lying comfortably, instead I was sitting upright, slightly teary-eyed...and by the end, there was popcorn on the floor and I was standing in front my television, gripping my remote tightly and shaking my head in disbelief. I immediately scrolled through Facebook to see if I was alone, and just as I imagined, I wasnt.

Several people with skin like mine who watched the film felt just like I did. Dont get me wrong, the movie was well done and the acting was superb, but it did something that I wasnt expecting. It evoked emotions that are still somewhat difficult for me to articulate. Simply put, I hurt for Henrietta Lacks and her family.

As I watched the movie, I thought to myself, why didnt I learn more about Henny (Henny because shes now my auntie in my head) in school? From grades 7-12, I attended a health sciences magnet school. In college, I was a biology major. To say I know a little something about HeLa is an understatement, but I honestly dont recall hearing much about the owner of those magical cells. Yes, magical. Black girl magic isnt just a hashtag, you know. But I digress. Like many Black women, Henrietta Lacks was an unknown hero who, thanks to the book and subsequent film about her life, is no longer an obscure entity. However, unlike the three heroines in one of my favorite movies, Hidden Figures, Henriettas story did not have such a happy ending.

Henrietta was diagnosed with cervical cancer and died from the disease at the age of 31. As a result, she left a special legacy and five children whose lives would never be the same. But it wasnt her untimely death that shocked me as that was quite common back in the day. No, it was the blatant disregard for her basic human rights that I found so appalling. To which human right am I referring? Henrietta was not given the right to consent, and even though it was not required at that time, ethically, she should have been asked for the use of her cells.

Picture this. Youre a young woman, lying in a hospital bed, gravely ill and undergoing treatment for a disease you dont fully understand. There are doctors and nurses coming in and out of your room. They are talking to you, smiling at you, and poking you with needles. They spread your legs to take a piece of your cervix so they can figure out how to fix you. Its ok because you trust them. But not one time do they ask you if they can use the cells from your body to learn more about your disease. No one takes the time to explain to you how the use of your cells could possibly benefit others for years to come. And after you pass away, no one consults your grieving family members to obtain permission to continue the use of your cells.

Mrs. Lacks, we need your permission for something. Can we use the cells from your biopsy for research? Theres a possibility that you could help us understand this disease better. You could also be helping others.

I imagine a conversation like that with Henrietta would have sufficed, but that didnt happen. So lets not sugarcoat it. Henriettas cells were stolen. Her cells were taken and used to advance research and medical practices and she went virtually unknown for years. And to make matters worse, her family still has not been properly compensated. Unbelievable, I know. Now, some may wonder whats so great about Henriettas cells anyway. Why does her family deserve anything after all of this time? Well, let me explain.

Henrietta cells, i.e., HeLa, were unique. You may say she was an ordinary woman with extraordinary cells. HeLa cells are an immortalized cell line, meaning the cells can be reproduced infinitely in a lab. Her cells have aided in the advancement of science and modern medicine tremendously. For example, the cells were used to develop the polio vaccine. In addition, they have been instrumental in HIV and cancer research. Oh, but it doesnt stop there. These cells even paved the way for in vitro fertilization, and the list goes on and on. And while I am thankful for the progress Henriettas cells have afforded medical research, the treatment of Blacks as guinea pigs in the past has left a very bitter taste in my mouth.

Real talk. What occurred to Henrietta wasnt an isolated incident. We all know about the Tuskegee Experiment the time scientists used Black men as lab animals to study the effects of Syphilis but I wonder just how many stories like Henriettas and the Tuskegee Experiment are still untold? And why have the contributions of so many Blacks been undervalued or erased from the history books? And lastly, why is health equity still so difficult to attain in 2017. What do I mean by that last question? Well, for example, Black women are still dying from breast and cervical cancers at higher rates than other ethnic/racial groups. The same goes for Black men and prostate cancer. I could go on but you get the point. The fact is, I dont know the answers to these questions, and as a public health professional, I am working everyday to identify solutions. But what I do know is this, modern medicine has a huge unpaid debt. The creditors are the descendants of Mrs. Henrietta Lacks, and I, for one, think its time to pay up.

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Henrietta Lacks And Modern Medicine's Greatest Unpaid Debt - Huffington Post