Ready, Set, Go: CIRM funded clinical trial for heart disease finishes patient enrollment

Heart disease is the leading cause of death in the United States with over 600,000 deaths occurring per year. Patients with heart disease or heart failure are given treatments that attempt to prevent their condition from getting worse or improve some of their symptoms. However, no treatment exists that can completely restore their heart function except for having a heart transplant – a risky procedure that has significant obstacles associated with it including transplant rejection and limited donor availability.

Regenerative medicine research for heart disease is an up-and-coming field. Scientist and companies are testing stem cell-based therapies to treat patients with heart disease in hopes of improving or restoring heart function.


CIRM is funding a company called Capricor Therapeutics located in Los Angeles, California, that’s testing a stem cell-based therapy in a Phase II clinical trial for cardiac dysfunction called ALLSTAR (ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration).  The treatment is called  CAP-1002, which is an infusion of allogeneic cardiosphere-derived cells (CDCs). Capricor has shown that CDCs can regenerate tissue in the injured human heart in a previous Phase I clinical trial called CADUCEUS, which treated patients one to three months after they had a heart attack.

This week, Capricor reported that it has passed another milestone in the ALLSTAR trial and finished patient enrollment. Compared to the CADUCEUS trial, the patient population in ALLSTAR was expanded to include individuals that had a heart attack in the past 12 months. The purpose of this expanded patient population is to determine whether CAP-1002 is beneficial to patients with older heart injuries. A total of 142 patients were enrolled in the trial and 134 of those patients received either a single injection of CAP-1002 or a placebo treatment into their coronary artery associated with the heart injury.

In a news release, Capricor President and CEO Linda Marban explained the logic behind the CADUCEUS and ALLSTAR trials for cardiac dysfunction:

Linda Marban, CEO of Capricor Therapeutics

Linda Marban, CEO of Capricor Therapeutics

“As we and others have shown, CAP-1002 possesses the ability to promote therapeutic regeneration in the injured heart, a powerful concept for the treatment of heart disease. In the CADUCEUS clinical trial, CDCs decreased scar size and increased viable tissue in the hearts of patients who had suffered a large heart attack. In ALLSTAR, not only are we studying a population similar to the one that delivered such astounding results in CADUCEUS (30 – 90 days post-MI), but we have also included patients that were 91 – 365 days post-MI to see if we could extend the indication window. We have also moved to an allogeneic platform from autologous cells.”

ALLSTAR patients will be monitored carefully over the next year to make sure the CAP-1002 treatment is safe. After a year, Capricor will assess the potential regenerative capacity of CAP-1002 by measuring the size of the heart injury and looking for a reduction in scar tissue using magnetic resonance imaging (MRI).

“With the last patient in ALLSTAR having been dosed on September 30th, we expect to report top-line 12-month primary efficacy outcome results in the fourth quarter of 2017,” said Marban. “We are very much looking forward to seeing the results of the ALLSTAR trial because they may show, for the first time in a Phase II clinical trial, that cells can reduce scar and potentially improve outcomes.”

CIRM is also funding another clinical trial by Capricor that’s evaluating CAP-1002 in young boys with cardiomyopathy – diseases that affect heart muscle – resulting from Duchenne muscular dystrophy. The Phase I/II trial called HOPE recently completed its patient enrollment and you can read more about it here on the Stem Cellar.

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Buildup of random mutations in adult stem cells doesn’t explain varying frequency of cancers

To divide or not to divide?

 It’s a question every cell in your body must constantly ask itself. Cells in your small intestine, for instance, replace themselves about every three days so the cells in that tissue must divide frequently to replenish the tissue. Liver cell are less active and turn over about once a year. And on the other extreme, the cells in the lens of the eye are kept over a life time.

The cell cycle, an exquisitely controlled process.

The cell cycle, an exquisitely controlled process. (Source wikipedia)

It’s no wonder that the process of cell division, also called the cell cycle, is exquisitely controlled by many different proteins and signaling molecules. It also makes sense that mutations in genes that produce the cell cycle proteins, could cause the regulation of cell division to go awry.

Mutations pave a path to cancer

Accumulation of enough mutations over a lifetime can lead to uncontrolled cell growth and eventually cancer. Adult stem cells are thought to be especially vulnerable to cell cycle mutations since these cells already have the capacity to self-renew and can pass mutations to their daughter cells.

Now, gene mutations can be inherited from one’s parents or caused by environmental factors like UV rays from the sun or acquired by random mistakes that occur as DNA replicates itself during cells division. Studying how the accumulation of these different mutation types impact cell division is important for understanding the formation of cancers. Results from a study in early 2015 indicated that mutations caused by random mistakes in DNA replication had a bigger impact on many cancers than mutations arising from lifestyle and environmental factors.

“Bad luck” mutations may not be the most harmful

But a new research publication in Nature suggests that, while these “bad luck” mutations can drive the development of cancer, they probably are not the main contributors. To reach this conclusion, the research team – which hails from the University Medical Center Utrecht in the Netherlands – directly measured mutation rates in human adult stem cells collected from donors as young as three years and as old as 87. In particular, stem cells from the liver, small intestine and colon were obtained. Individual stem cells were grown in the lab into mini-organs, or organoids, that resemble the structures of the source tissue. After studying these organoids, they determined that the frequency of cancer is very different in these organs, with the incidence cancer in the colon being much higher than in the other two organs.

Mutation rate the same, despite age, despite organ type

Through a various genetic analyses, the team found that an interesting pattern: the mutation rate was the same – about 40 mutations per year – for all organ types and all ages despite the higher incidence of colon cancer and older age-related cancers. Dr. Ruben van Boxtel, the team leader, expressed his reaction to these results in an interview with Medical News Today:

“We were surprised to find roughly the same mutation rate in stem cells from organs with different cancer incidence. This suggests that simply the gradual accumulation of more and more ‘bad luck’ DNA errors over time cannot explain the difference we see in cancer incidence – at least for some cancers.”

Still, the team did observe that different types of random mutations were specific to one organ over the other. These differences may help explain why the colon, for example, has a higher cancer incidence than the liver or small intestine. Van Boxtel and his team are interested in examining this result further:

“It seems ‘bad luck’ is definitely part of the story but we need much more evidence to find out how, and to what extent. This is what we want to focus on next.”

From Pig Parts to Stem Cells: Scientist Douglas Melton Wins Ogawa-Yamanaka Prize for Work on Diabetes

Since the 1920s, insulin injections have remained the best solution for managing type 1 diabetes. Patients with this disease do not make enough insulin – a hormone that regulates the sugar levels in your blood – because the insulin-producing cells, or beta cells, in their pancreas are destroyed.

Back then, it took two tons of pig parts to make eight ounces of insulin, which was enough to treat 10,000 diabetic patients for six months. Biotech and pharmaceutical companies have since developed different types of human insulin treatments that include fast and long acting versions of the hormone. It’s estimated that $22 billion will be spent on developing insulin products for patients this year and that costs will rise to $32 billion in the year 2019.

These costs are necessary to keep insulin-dependent diabetes patients alive and healthy, but what if there was a different, potentially simpler solution to manage diabetes? One that looks to insulin-producing beta cells as the solution rather than daily hormone shots?

Douglas Melton Receives Stem Cell Prize for Work on Diabetes

Harvard scientist Douglas Melton envisions a world where one day, insulin-dependent diabetic patients are given stem cell transplants rather than shots to manage their diabetes. In the 90s, Melton’s son was diagnosed with type 1 diabetes. Motivated by his son’s diagnosis, Melton dedicated the focus of his research on understanding how beta cells develop from stem cells in the body and also in a cell culture dish.

Almost 30 years later, Melton has made huge strides towards understanding the biology of beta cell development and has generated methods to “reprogram” or coax pluripotent stem cells into human beta cells.

Melton was honored for his important contributions to stem cell and diabetes research at the second annual Ogawa-Yamanaka Stem Cell Prize ceremony last week at the Gladstone Institutes. This award recognizes outstanding scientists that are translating stem cell research from the lab to clinical trials in patients.


Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, explained why Melton was selected as this year’s prize winner:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“Doug’s research on genetic markers expressed during pancreas development have led to a reliable way to reprogram stem cells into human beta cells. His work provides the foundation for the ultimate goal of transplantable, patient-specific beta cells.”


Making Beta Cells for Patients

During the awards ceremony, Melton discussed his latest work on generating beta cells from human stem cells and how this technology could transform the way insulin-dependent patients are treated.

Douglas Melton, Harvard University.

Douglas Melton, Harvard University.

“I don’t mean to say that this [insulin treatment] isn’t a good idea. That’s keeping these people alive and in good health,” said Melton during his lecture. “What I want to talk about is a different approach. Rather than making more and better insulins and providing them by different medical devices, why not go back to nature’s solution which is the beta cells that makes the insulin?”

Melton first described his initial research on making pancreatic beta cells from embryonic and induced pluripotent stem cells in a culture dish. He described the power of this system for not only modeling diabetes, but also screening for potential drugs, and testing new therapies in animal models.

He also mentioned how he and his colleagues are developing methods to manufacture large amounts of human beta cells derived from pluripotent stem cells for use in patients. They are able to culture stem cells in large spinning flasks that accelerate the growth and development of pluripotent stem cells into billions of human beta cells.

Challenges and Future of Stem-Cell Derived Diabetes Treatments

Melton expressed a positive outlook for the future of stem cell-derived treatments for insulin-dependent diabetes, but he also mentioned two major challenges. The first is the need for better control over the methods that make beta cells from stem cells. These methods could be more efficient and generate higher numbers of beta cells (beta cells make up 16% of stem cell-derived cells using their current culturing methods). The second is preventing an autoimmune attack after transplanting the stem-cell derived beta cells into patients.

Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.


He mentioned a CIRM-funded clinical trial by ViaCyte, which is testing an encapsulation device that is placed under the skin. The device contains embryonic stem cell-derived pancreatic progenitor cells that develop into beta cells that secrete insulin into the blood stream. The device also prevents the immune system from attacking and killing the beta cells.

Melton also discussed a biological approach to protecting transplanted beta cells. In collaboration with Dan Anderson at MIT, they coated stem cell-derived beta cells in a biomaterial called alginate, which comes from seaweed. They injected alginate microcapsule-containing beta cells into diabetic mice and were able control their blood sugar levels.

At the end of his talk, Melton concluded that he believes that beta cell transplantation in an immunoprotective device containing stem cell-derived cells will have the most benefit for diabetes patients.

Gladstone Youtube video of Douglas Melton’s lecture at the Ogawa-Yamanaka Prize lecture.

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Stem cell stories that caught our eye: healing diabetic ulcers, new spinal cord injury insights & an expanding CRISPR toolbox

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Stem cells heal diabetic foot ulcers in pilot study
Foot ulcers are one of the many long-term complications that diabetics face. About 15 percent of patients develop these open sores which typically appear at the bottom of the foot. In a quarter of these cases, the ulcers lead to serious infection requiring amputation.


Diabetic foot ulcers are open sores that don’t heal and in many cases leads to amputation. Image source: Izunpharma

But help may be on the horizon in the form of stem cells. Researchers at Mansoura University in Egypt recently presented results of a small study in which 10 patients with diabetic foot ulcers received standard care and another 10 patients received standard care plus injections of mesenchymal stem cells that had been collected from each patient’s own bone marrow. After just six weeks, the stem cell treated group showed a 50% reduction in the foot ulcers while the group with only standard care had a mere 7% reduction.

These superior results with the stem cells were observed even though the group receiving the stem cells had larger foot ulcers to begin with compared to the untreated patients. There are many examples of mesenchymal stem cells’ healing power which make them an extremely popular cell source for hundreds of on-going clinical trials. Mesenchymal stem cells are known to reduce inflammation and increase blood vessel formation, two properties that may be at work to give diabetic foot ulcers the chance to get better.

Medscape Medical News reported on these results which were presented at the 2016 annual meeting of the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting

Suppressing nerve signals to help spinal cord injury victims
Losing the use of one’s limbs is a profound life-altering change for spinal cord injury victims. But their quality of life also suffers tremendously from the loss of bladder control and chronic pain sensations. So much so, victims often say that just improving these secondary symptoms would make a huge improvement in their lives.

While current stem cell-based clinical trials, like the CIRM-funded Asterias study, aim to reverse paralysis by restoring loss nerve signals, recent CIRM-funded animal data published in Cell Stem Cell from UC San Francisco suggest that nerve cells that naturally suppress nerve signals may be helpful for these other symptoms of spinal cord injury.


Mature inhibitory neuron derived from human embryonic stem cells is shown after successfully migrated and integrated into the injured mouse spinal cord.
Photo by Jiadong Chen, UCSF

It turns out that the bladder control loss and chronic pain may be due to overactive nerve signals. So the lab of Arnold Kriegstein transplanted inhibitory nerve cells – derived from human embryonic stem cells – into mice with spinal cord injuries. The scientists observed that these human inhibitory nerve cells, or interneurons, successfully made working connections in the damaged mouse spinal cords. The rewiring introduced by these interneurons also led to reduced pain behaviors in the mice as well as improvements in bladder control.



In a Yahoo Finance interview, Kreigstein told reporters he’s eager to push forward with these intriguing results:


Arnold Kriegstein, UCSF

“As a clinician, I’m very aware of the urgency that’s felt among patients who are often very desperate for treatment. As a result, we’re very interested in accelerating this work toward clinical trials as soon as possible, but there are many steps along the way. We have to demonstrate that this is safe, as well as replicating it in other animals. This involves scaling up the production of these human interneurons in a way that would be compatible with a clinical product.”


Expanding the CRISPR toolbox
If science had a fashion week, the relatively new gene editing technology called CRISPR/Cas9 would be sure to dominate the runway. You can think of CRISPR/Cas9 as a protein and RNA complex that acts as a molecular scissor which directly targets and cuts specific sequences of DNA in the human genome. Scientists are using CRISPR/Cas9 to develop innovative biomedical techniques such as removing disease-causing mutations in stem cells in hopes of developing potential treatments for patients suffering from diseases that have no cures.

What’s particularly interesting about the CRISPR/Cas9 system is that the Cas9 protein responsible for cutting DNA is part of a family of CRISPR associated proteins (Cas) that have similar but slightly different functions. Scientists are currently expanding the CRISPR toolbox by exploring the functions of other CRISPR associated proteins for gene editing applications.

A CIRM-funded team at UC Berkeley is particularly interested in a CRISPR protein called C2c2, which is different from Cas9 in that it targets and cuts RNA rather than DNA. Led by Berkeley professor Jennifer Doudna, the team discovered that the CRISPR/C2c2 complex has not just one, but two, distinct ways that it cuts RNA. Their findings were published this week in the journal Nature.

The first way involves creation: C2c2 helps make the guide RNAs that are used to find the RNA molecules that it wants to cut. The second way involves destruction: after the CRISPR/C2c2 complex finds it’s RNAs of choice, C2c2 can then cut and destroy the RNAs.

Doudna commented on the potential applications for this newly added CRISPR tool in a Berkeley News release:


Jennifer Doudna: Photo courtesy of

“This study expands our molecular understanding of C2c2 to guide RNA processing and provides the first application of this novel RNase. C2c2 is essentially a self-arming sentinel that attacks all RNAs upon detecting its target. This activity can be harnessed as an auto-amplifying detector that may be useful as a low-cost diagnostic.”


A Patient Advocate’s Take on Sickle Cell Disease: The Pain and the Promise

September is National Sickle Cell Awareness Month. First officially recognized by the federal government in 1983, National Sickle Cell Awareness Month calls attention to sickle cell disease (SCD), a genetic disease that researchers estimate affects between 90,000 and 100,000 Americans. CIRM is funding a clinical trial focused on curing the disease with a stem cell-based gene therapy. 

People with this debilitating condition face a number of barriers in getting the help they need to keep their pain under control. In addition to the difficulty of accessing medication, they often have to overcome suspicion and discrimination.  Patient Advocate Nancy Rene, of Axis Advocacy  wrote the following blog about the problems families with SCD face.

Sickle Cell Disease Patient Advocates Adrienne Shapiro and Nancy Rene.

Sickle Cell Disease Patient Advocates Adrienne Shapiro and Nancy Rene.

Sickle Cell Disease: The Pain and the Promise

By Nancy M. Rene, co-founder, Axis Advocacy

The Disease

Sickle Cell Disease is a group of inherited red blood cell disorders. It is the most common genetic disease in the US. Close to 100,000 Americans have sickle cell disease.  Although it affects persons of African descent, it can also be found in Latino families and families from the Middle-East and India. World-wide there are at least 20 million people with the disease.

Normal red blood cells are round like doughnuts, and they move through small blood vessels in the body to deliver oxygen. Red blood cells in the person with sickle cell disease become hard, sticky and shaped like sickles. When these hard and pointed red cells go through the small blood vessels, they clog the flow and break apart. This causes pain, inflammation and organ damage.

The Pain and the Promise

In the last 30 years the United States has made great progress in treating sickle cell disease.  All states now have newborn screening and most children are living to adulthood. However, many children with SCD don’t receive important services to prevent serious complications from the disease.

Unfortunately, according the the American Society of Hematology, the mortality rate for adults appears to have increased during the same 30 years! Patients with SCD experience long delays in the ER, and are often accused of being drug seekers. Once admitted to the hospital they are confronted by medical staff with little understanding or empathy. Research from Dr. Michael DeBaun found that adults with this disease lack access to a primary care doctor who is knowledgeable about sickle cell.

The biggest Pain for those with sickle cell disease does not come from the disease itself but from treatment by the medical community.  When, for most people, going to the hospital represents a place to get help and relief from the burdens of a challenging disease, those with sickle cell see going to the hospital as going into battle. They “gear up” with copies of medical records and NIH guidelines, they make sure they have a diary to record inappropriate remarks from medical staff, they ask a friend to come along as an advocate to help them withstand the implied racism and institutional bias with which they are confronted. Even when new hospitals or clinics are built, they often do not live up to expectations, offering no emergency support or 24-hour access.

The promise of course comes from the diligent work of researchers and clinicians who run model programs.  Bone marrow transplants, while limited in use, have actually cured a number of young people, saving them from pain and organ damage that await their adult years. Pharmaceutical companies are completing clinical trials on several drugs that can reduce the symptoms of sickle cell at the molecular level. These drugs could greatly reduce the effects of the sickle cell crisis which often results in a lengthy hospital stay.

Stem cell research, while moving slowly, can be the holy grail of medical practice, curing many of the 100,000 Americans with sickle cell.  A cure would lead to avoiding the dreaded ER, being free of pain and organ damage, living a healthy life, and having children without worrying that they too would be born with this disease.

What is missing is linking research to clinical practice.  It is clear that the CDC, FDA and NIH have finally understood this missing piece.  The NIH published an extensive report, Guidelines for the The Treatment of Sickle Cell Disease, in 2014. NIH convened the 10th Annual Focus on Sickle Cell that brought researchers, clinicians, and other leaders together to make presentations on their work in sickle cell. The Sickle Cell Research Foundation convened an outstanding medical conference in Florida that again brought leaders together to gain knowledge from one another. ASH, the American Society of Hematology, is planning to launch a Sickle Cell Initiative this month.

We in the sickle cell community, patients, care-givers, and advocates, feel that we have finally got some big guns in this fight. Once doctors in all communities understand this disease, once they are aware of their own implicit bias and that of their institutions, there should be improvement in the treatment of people with this painful, debilitating illness.

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Gene required for sperm stem cells linked to male infertility, UCSD study suggests

Even in this day and age, when a couple is having trouble conceiving a child, it’s often the woman who is initially suspected of having infertility problems and is likely the first to seek out the advice of doctor. But according to Miles Wilkinson, professor of reproductive medicine at UC San Diego School of Medicine, infertility issues can just as likely be due to problems with sperm production in the male. In fact, about 4 million men of reproductive age in the U.S. are confronted with infertility challenges and in 30% percent of those cases, the cause of the infertility is not well understood.

Through some scientific detective work, Wilkinson and his research team have zeroed in on a gene called RhoX10 that plays an essential role in the development of adult stem cells which give rise to sperm production. The study results, funded in part by CIRM and published yesterday in Cell Reports, may help provide a path toward new treatment options for male infertility.


The process of sperm formation (spermatogenesis). Image: Wikipedia

To get at a cellular and molecular understanding of infertility, the team focused on the function of spermatogonial stem cells (SSCs). Through a multistep process within the male reproductive system, SSCs form into mature sperm cells capable of fertilizing an egg.  The SSC itself forms from primordial germ cells. The key genetic switches that help these germ cells give rise to SSCs was not well understood.  Earlier studies had shown that a group of adjacent genes, called the Rhox cluster, on the X-chromosome are expressed in the testes, suggesting a role in sperm production.

Using genetic engineering techniques, Wilkinson’s team bred mice lacking the 33 genes of the Rhox cluster. The resulting male mice showed a reduction in the number SSCs leading to low sperm number. Through a process of elimination, the team found that deleting just one of those genes, Rhox10, produced nearly the same flaw.

Rhox10 bus_HW, 9-26-16.jpg.jpg

Rhox 10: a genetic “bus” that “drives” sperm stem cells toward sperm production. Illustration by Hye-Won Song.

Further analysis, indicated Rhox10 was key to driving the development of germ cells into SSCs. So when the gene is deleted, not enough SSCs develop in the testis, leading to low sperm counts.  The researchers also found the Rhox10 is a master regulator of genes that control the germ cells’ movement from one part of the testis to another that, due to a different chemical environment, helps the germ cells transform into SSCs.

In addition to this mouse data, the team also co-authored a recent Human Molecular Genetics report with scientists at the University of Münster in Germany that connects Rhox genes and human male infertility. In the study, three RHOX genes were sequenced in 250 men with extremely low sperm counts and revealed six genetic mutations. Together, these results present solid evidence that mutations in Rhox are the culprit in at least some forms of male infertility. First author Hye-Won Song discussed this point in a university press release:

“Spermatogonial stem cells allow men — even in their 70s — to generate sperm and father children. Our finding that Rhox10 is critical for spermatogonial stem cells, coupled with the finding that human RHOX genes are mutated in infertile men, suggests that mutations in these genes cause human male infertility.”

Stem Cell Experts Discuss the Ethical Implications of Translating iPSCs to the Clinic

Part of The Stem Cellar blog series on 10 years of iPSCs.

This year, scientists are celebrating the 10-year anniversary of Shinya Yamanaka’s Nobel Prize winning discovery of induced pluripotent stem cells (iPSCs). These are cells that are very similar biologically to embryonic stem cells and can develop into any cell in the body. iPSCs are very useful in scientific research for disease modeling, drug screening, and for potential cell therapy applications.

However, with any therapy that involves testing in human patients, there are ethical questions that scientists, companies, and policy makers must consider. Yesterday, a panel of stem cell and bioethics experts at the Cell Symposium 10 Years of iPSCs conference in Berkeley discussed the ethical issues surrounding the translation of iPSC research from the lab bench to clinical trials in patients.

The panel included Shinya Yamanaka (Gladstone Institutes), George Daley (Harvard University), Christine Mummery (Leiden University Medical Centre), Lorenz Studer (Memorial Sloan Kettering Cancer Center), Deepak Srivastava (Gladstone Institutes), and Bioethicist Hank Greely (Stanford University).

iPSC Ethics Panel

iPSC Ethics Panel at the 10 Years of iPSCs Conference

Below is a summary of what these experts had to say about questions ranging from the ethics of patient and donor consent, genetic modification of iPSCs, designer organs, and whether patients should pay to participate in clinical trials.

How should we address patient or donor consent regarding iPSC banking?

Multiple institutes including CIRM are developing iPSC banks that store thousands of patient-derived iPSC lines, which scientists can use to study disease and develop new therapies. These important cell lines wouldn’t exist without patients who consent to donate their cells or tissue. The first question posed to the panel was how to regulate the consent process.

Christine Mummery began by emphasizing that it’s essential that companies are able to license patient-derived iPSC lines so they don’t have to go back to the patient and inconvenience them by asking for additional samples to make new cell lines.

George Daley and Hank Greely discussed different options for improving the informed consent process. Daley mentioned that the International Society for Stem Cell Research (ISSCR) recently updated their informed consent guidelines and now provide adaptable informed consent templates that can be used for obtaining many type of materials for human stem cell research.  Daley also mentioned the move towards standardizing the informed consent process through a single video shared by multiple institutions.

Greely agreed that video could be a powerful way to connect with patients by using talented “explainers” to educate patients. But both Daley and Greely cautioned that it’s essential to make sure that patients understand what they are getting involved in when they donate their tissue.

Greely rounded up the conversation by reminding the audience that patients are giving the research field invaluable information so we should consider giving back in return. While we can’t and shouldn’t promise a cure, we can give back in other ways like recognizing the contributions of specific patients or disease communities.

Greely mentioned the resolution with Henrietta Lack’s family as a good example. For more than 60 years, scientists have used a cancer cell line called HeLa cells that were derived from the cervical cancer cells of a woman named Henrietta Lacks. Henrietta never gave consent for her cells to be used and her family had no clue that pieces of Henrietta were being studied around the world until years later.

In 2013, the NIH finally rectified this issue by requiring that researchers ask for permission to access Henrietta’s genomic data and to include the Lacks family in their publication acknowledgements.

Hank Greely, Stanford University

Hank Greely, Stanford University

“The Lacks family are quite proud and pleased that their mother, grandmother and great grandmother is being remembered, that they are consulted on various things,” said Hank Greely. “They aren’t making any direct money out of it but they are taking a great deal of pride in the recognition that their family is getting. I think that returning something to patients is a nice thing, and a human thing.”

What are the ethical issues surrounding genome editing of iPSCs?

The conversation quickly focused on the ongoing CRISPR patent battle between the Broad Institute, MIT and UC Berkeley. For those unfamiliar with the technique, CRISPR is a gene editing technology that allows you to cut and paste DNA at precise locations in the genome. CRISPR has many uses in research, but in the context of iPSCs, scientists are using CRISPR to remove disease-causing mutations in patient iPSCs.

George Daley expressed his worry about a potential fallout if the CRISPR battle goes a certain way. He commented, “It’s deeply concerning when such a fundamentally enabling platform technology could be restricted for future gene editing applications.”

The CRISPR patent battle began in 2012 and millions of dollars in legal fees have been spent since then. Hank Greely said that he can’t understand why the Institutes haven’t settled this case already as the costs will only continue to rise, but that it might not matter how the case turns out in the end:

“My guess is that this isn’t ultimately going to be important because people will quickly figure out ways to invent around the CRISPR/Cas9 technology. People have already done it around the Cas9 part and there will probably be ways to do the same thing for the CRISPR part.”

 Christine Mummery finished off with a final point about the potential risk of trying to correct disease causing mutations in patient iPSCs using CRISPR technology. She noted that it’s possible the correction may not lead to an improvement because of other disease-causing genetic mutations in the cells that the patient and their family are unaware of.

 Should patients or donors be paid for their cells and tissue?

Lorenz Studer said he would support patients being paid for donating samples as long as the payment is reasonable, the consent form is clear, and patients aren’t trying to make money off of the process.

Hank Greely said the big issue is with inducement and whether you are paying enough money to convince people to do something they shouldn’t or wouldn’t want to do. He said this issue comes up mainly around reproductive egg donation but not with obtaining simpler tissue samples like skin biopsies. Egg donors are given money because it’s an invasive procedure, but also because a political decision was made to compensate egg donors. Greely predicts the same thing is unlikely to happen with other cell and tissue types.

Christine Mummery’s opinion was that if a patient’s iPSCs are used by a drug company to produce new successful drugs, the patient should receive some form of compensation. But she said it’s hard to know how much to pay patients, and this question was left unanswered by the panel.

Should patients pay to participate in clinical trials?

George Daley said it’s hard to justify charging patients to participate in a Phase 1 clinical trial where the focus is on testing the safety of a therapy without any guarantee that there will be beneficial outcome to the patient. In this case, charging a patient money could raise their expectations and mislead them into thinking they will benefit from the treatment. It would also be unfair because only patients who can afford to pay would have access to trials. Ultimately, he concluded that making patients pay for an early stage trial would corrupt the informed consent process. However, he did say that there are certain, rare contexts that would be highly regulated where patients could pay to participate in trials in an ethical way.

Lorenz Studer said the issue is very challenging. He knows of patients who want to pay to be in trials for treatments they hope will work, but he also doesn’t think that patients should have to pay to be in early stage trials where their participation helps the progress of the therapy. He said the focus should be on enrolling the right patient groups in clinical trials and making sure patients are properly educated about the trial they are participating.

Thoughts on the ethics behind making designer organs from iPSCs?

Deepak Srivastava said that he thinks about this question all the time in reference to the heart:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“The heart is basically a pump. When we traditionally thought about whether we could make a human heart, we asked if we could make the same thing with the same shape and design. But in fact, that’s not necessarily the best design – it’s what evolution gave us. What we really need is a pump that’s electrically active. I think going forward, we should remove the constraint of the current design and just think about what would be the best functional structure to do it. But it is definitely messing with nature and what evolution has given us.”

Deepak also said that because every organ is different, different strategies should be used. In the case of the heart, it might be beneficial to convert existing heart tissue into beating heart cells using drugs rather than transplant iPSC-derived heart cells or tissue. For other organs like the pancreas, it is beneficial to transplant stem cell-derived cells. For diabetes, scientists have shown that injecting insulin secreting cells in multiple areas of the body is beneficial to Diabetes patients.

Hank Greely concluded that the big ethical issue of creating stem cell-derived organs is safety. “Biology isn’t the same as design,” Greely said. “It’s really, really complicated. When you put something into a biological organism, the chances that something odd will happen are extremely high. We have to be very careful to avoid making matters worse.”

For more on the 10 years of iPSCs conference, check out the #CSStemCell16 hashtag on twitter.

Full Steam Ahead: First Patient is Dosed in Expanded CIRM Spinal Cord Injury Trial

Today we bring you more good news about a CIRM-funded clinical trial for spinal cord injury that’s received a lot of attention lately in the news. Asterias Biotherapeutics has treated its first patient in an expanded patient population of spinal cord injury patients who suffer from cervical, or neck, injuries.

In late August, Asterias reported that they had passed the first hurdle in their Phase 1/2a trial and showed that their stem cell therapy is safe to use in patients with a more serious form of cervical spinal cord injuries.

Earlier this month, we received more exciting updates from Asterias – this time reporting that the their embryonic stem cell-based therapy, called AST-OPC1, appeared to benefit treated patients. Five patients with severe spinal cord injuries to their neck were dosed, or transplanted, with 10 million cells. These patients are classified as AIS-A on the ASIA impairment scale – meaning they have complete injuries in which the spinal cord tissue is severed and patients lose all feeling and use of their limbs below the injury site. Amazingly, after three months, all five of the AIS-A patients have seen improvements in their movement.

Today, Asterias announced that it has treated its first patient with an AIS-B grade cervical spinal cord injury with a dose of 10 million cells at the Sheperd Center in Atlanta. AIS-B patients have incomplete neck injuries, meaning that they still have some spinal cord tissue at the injury site, some feeling in their arms and legs, but no movement. This type of spinal cord injury is still severe, but these patients have a better chance at gaining back some of their function and movement after treatment.

In a press release by Asterias, Chief Medical Officer Dr. Edward Wirth said:

“We have been very encouraged by the first look at the early efficacy data, as well as the safety profile, for AST-OPC1 in AIS-A patients, and now look forward to also evaluating efficacy and safety in AIS-B patients. AIS-B patients also have severe spinal cord injuries, but compared to AIS-A patients they have more spared tissue in their spinal cords.  This may allow these patients to have a greater chance of meaningful functional improvement after being treated with AST-OPC1 cells.”

Dr. Donald Peck Leslie, who directs the Sheperd Center and is the lead investigator at the Atlanta clinical trial site, expressed his excitement about the trials’ progress.

“As someone who regularly treats patients who have sustained paralyzing spinal cord injuries, I am encouraged by the progress we’ve seen in evaluations of AST-OPC1 in people with AIS-A injuries, particularly the improvements in hand, finger and arm function. Now, I am looking forward to continuing the evaluation of this promising new treatment in AIS-B patients, as well.”

Asterias has plans to enroll a total of five to eight AIS-B patients who will receive a dose of 10 million cells. They will continue to monitor all patients in this trial (both AIS-A and B) and will conduct long-term follow up studies to make sure that the AST-OPC1 treatment remains safe.

We hope that the brave patients who have participated in the Asterias trial continue to show improvements following treatment. Inspiring stories like that of Kris Boesen, who was the first AIS-A patient to get 10 million cells in the Asterias trial and now has regained the use of his arms and hands (and regaining some sensation in his legs), are the reason why CIRM exists and why we are working so hard to fund promising clinical trials. If we can develop even one stem cell therapy that gives patients back their life, then our efforts here at CIRM will be worthwhile.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

Kris Boesen, CIRM spinal cord injury clinical trial patient.

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Stem cell stories that caught our eye: two studies of the heart and cool stem cell art

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Image from Scope Blog.

Image from Scope Blog.

Understanding Heart Defects. Healthy heart tissue is made up of smooth, solid muscle, which is essential for normal heart function. Patients with a heart defect called left ventricular non-compaction (LVNC), lack normal heart tissue in their left ventricle – the largest, strongest blood-pumping chamber – and instead have spongy-looking tissue.

LVNC occurs during early heart development where pieces of heart muscle fail to condense (compact) and instead form an airy, sponge-like network that can leave patients at risk for heart failure and other complications.

A team at Stanford is interested in learning how LVNC occurs in humans, and they’re using human stem cells for the answer. Led by CIRM grantee Joe Wu, the scientists generated induced pluripotent stem cells (iPSCs) from four patients with LVNC. iPSCs are cells that can be turned into any other cell in the body, so Wu turned these cells into iPSC-derived heart muscle in a dish.

Wu’s team was particularly interested in determining why some LVNC patients have symptoms of disease while others seem perfectly normal. After studying the heart muscle cells derived from the four LVNC patients, they identified a genetic mutation in a gene called TBX20. This gene produces a type of protein called a cardiac transcription factor, which controls the expression of other heart related genes.

Upon further exploration, the scientists found that the genetic mutation in TBX20 prevented LVNC heart muscle cells from dividing at their normal rate. If they blocked the signal of mutant TBX20, the heart cells went back to their normal activity and created healthy looking heart tissue.

This study was published in Nature Cell Biology and covered by the Stanford Medicine Scope blog. In an interview with Scope, Joe Wu highlighted the big picture of their work:

Joseph Wu Stanford

Joseph Wu Stanford

“This study shows the feasibility of modeling such developmental defects using human tissue-specific cells, rather than relying on animal cells or animal models. It opens up an exciting new avenue for research into congenital heart disease that could help literally the youngest — in utero — patients.”

Stem Cell Heart Patch. Scientists from the University of Wisconsin, Madison are creating stem cell-based heart patches that they hope one day could be used to treat heart disease.

In a collaboration with Duke and the University of Alabama at Birmingham, they’re developing 3D stem cell-derived patches that contain the three main cell types found in the heart: cardiomyocytes (heart muscle cells), fibroblasts (support cells), and endothelial cells (cells that line the insides of blood vessels). These patches would be transplanted into heart disease patients to replace damaged heart tissue and improve heart function.

As with all research that has the potential for reaching human patients, the scientists must first determine whether the heart patches are safe in animal models. They plan to transplant the heart patches into a pig model – chosen because pigs have similar sized hearts compared to humans.

In a UW-Madison News release, the director of the UW-Madison Stem Cell and Regenerative Medicine Center Timothy Kamp, hinted at the potential for this technology to reach the clinic.

“The excitement here is we’re moving closer to patient applications. We’re at a stage when we need to see how these cells do in a large animal heart attack model. We’ll be making patches of heart muscle that can be applied to these injured areas.”

Kamp and his team still have a lot of work to do to perfect their heart patch technology, but they are thinking ahead. Two issues that they are trying to address are how to prevent a patient’s immune system from rejecting the heart patch transplant, and how to make sure the heart patches beat in sync with the heart they are transplanted into.

Check out the heart patches in action in this video:

(Video courtesy of Xiaojun Lian)

Cool Stem Cell Art! When I was a scientist, I worked with stem cells all the time. I grew them in cell culture dishes, coaxed them to differentiate into brain cells, and used a technique called immunostaining to take really beautiful, colorful pictures of my final cell products. I took probably thousands of pictures over my PhD and postdoc, but sadly, only a handful of these photos ever made it into journal publications. The rest collected dust either on my hard drive or in my lab notebook.

It’s really too bad that at the time I didn’t know about this awesome stem cell art contest called Cells I See run by the Centre for Commercialization of Regenerative Medicine (CCRM) in Ontario Canada and sponsored by the Stem Cell Network.

The contest “is about the beauty of stem cells and biomaterials, seen directly through the microscope or through the interpretive lens of the artist.” Scientists can submit their most prized stem cell images or art, and the winner receives a cash prize and major science-art street cred.

The submission deadline for this year’s contest was earlier this month, and you can check out the contenders on CCRM’s Facebook page. Even better, you can vote for your favorite image or art by liking the photo. The last date to vote is October 15th and the scientist whose image has the most likes will be the People’s Choice winner. CCRM will also crown a Grand Prize winner at the Till & McCulloch Stem Cell Meeting in October.

I’ll leave you with a few of my favorite photos, but please don’t let this bias your vote =)!

"Icy Astrocytes" by Samantha Yammine

“Icy Astrocytes” by Samantha Yammine (Vote here!)

"Reaching for organoids" by Amy Wong

“Reaching for organoids” by Amy Wong (Vote here!)

"Iris" by Sabiha Hacibekiroglu

“Iris” by Sabiha Hacibekiroglu (Vote here!)

Funding stem cell research targeting a rare and life-threatening disease in children


Photo courtesy Cystinosis Research Network

If you have never heard of cystinosis you should consider yourself fortunate. It’s a rare condition caused by an inherited genetic mutation. It hits early and it hits hard. Children with cystinosis are usually diagnosed before age 2 and are in end-stage kidney failure by the time they are 9. If that’s not bad enough they also experience damage to their eyes, liver, muscles, pancreas and brain.

The genetic mutation behind the condition results in an amino acid, cystine, accumulating at toxic levels in the body. There’s no cure. There is one approved treatment but it only delays progression of the disease, has some serious side effects of its own, and doesn’t prevent the need for a  kidney transplant.

Researchers at UC San Diego, led by Stephanie Cherqui, think they might have a better approach, one that could offer a single, life-long treatment for the problem. Yesterday the CIRM Board agreed and approved more than $5.2 million for Cherqui and her team to do the pre-clinical testing and work needed to get this potential treatment ready for a clinical trial.

Their goal is to take blood stem cells from people with cystinosis, genetically-modify them and return them to the patient, effectively delivering a healthy, functional gene to the body. The hope is that these genetically-modified blood stem cells will integrate with various body organs and not only replace diseased cells but also rescue them from the disease, making them healthy once again.

In a news release Randy Mills, CIRM’s President and CEO, said orphan diseases like cystinosis may not affect large numbers of people but are no less deserving of research in finding an effective therapy:

“Current treatments are expensive and limited. We want to push beyond and help find a life-long treatment, one that could prevent kidney failure and the need for kidney transplant. In this case, both the need and the science were compelling.”

The beauty of work like this is that, if successful, a one-time treatment could last a lifetime, eliminating or reducing kidney disease and the need for kidney transplantation. But it doesn’t stop there. The lessons learned through research like this might also apply to other inherited multi-organ degenerative disorders.