Rare Disease, Type 1 Diabetes, and Heart Function: Breakthroughs for Three CIRM-Funded Studies

This past week, there has been a lot of mention of CIRM funded studies that really highlight the importance of the work we support and the different disease areas we make an impact on. This includes important research related to rare disease, Type 1 Diabetes (T1D), and heart function. Below is a summary of the promising CIRM-funded studies released this past week for each one of these areas.

Rare Disease

Comparison of normal (left) and Pelizaeus-Merzbacher disease (PMD) brains (right) at age 2. 

Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting boys. It can be fatal before 10 years of age and symptoms of the disease include weakness and breathing difficulties. PMD is caused by a disruption in the formation of myelin, a type of insulation around nerve fibers that allows electrical signals in the brain to travel quickly. Without proper signaling, the brain has difficulty communicating with the rest of the body. Despite knowing what causes PMD, it has been difficult to understand why there is a disruption of myelin formation in the first place.

However, in a CIRM-funded study, Dr. David Rowitch, alongside a team of researchers at UCSF, Stanford, and the University of Cambridge, has been developing potential stem cell therapies to reverse or prevent myelin loss in PMD patients.

Two new studies, of which Dr. Rowitch is the primary author, published in Cell Stem Cell, and Stem Cell Reports, respectively report promising progress in using stem cells derived from patients to identify novel PMD drugs and in efforts to treat the disease by directly transplanting neural stem cells into patients’ brains. 

In a UCSF press release, Dr. Rowitch talks about the implications of his findings, stating that,

“Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.”

Type 1 Diabetes

Viacyte, a company that is developing a treatment for Type 1 Diabetes (T1D), announced in a press release that the company presented preliminary data from a CIRM-funded clinical trial that shows promising results. T1D is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin, a hormone that enables our bodies to break down sugar in the blood. CIRM has been funding ViaCyte from it’s very earliest days, investing more than $72 million into the company.

The study uses pancreatic precursor cells, which are derived from stem cells, and implants them into patients in an encapsulation device. The preliminary data showed that the implanted cells, when effectively engrafted, are capable of producing circulating C-peptide, a biomarker for insulin, in patients with T1D. Optimization of the procedure needs to be explored further.

“This is encouraging news,” said Dr. Maria Millan, President and CEO of CIRM. “We are very aware of the major biologic and technical challenges of an implantable cell therapy for Type 1 Diabetes, so this early biologic signal in patients is an important step for the Viacyte program.”

Heart Function

Although various genome studies have uncovered over 500 genetic variants linked to heart function, such as irregular heart rhythms and heart rate, it has been unclear exactly how they influence heart function.

In a CIRM-funded study, Dr. Kelly Frazer and her team at UCSD studied this link further by deriving heart cells from induced pluripotent stem cells. These stem cells were in turn derived from skin samples of seven family members. After conducting extensive genome-wide analysis, the team discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.

In a press release by UCSD, Dr. Frazer elaborated on the important role this protein plays by stating that,

“NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function. As a result, we are finding that multiple heart-related traits can share a common mechanism — in this case, differential binding of NKX2-5 due to DNA variants.”

The full results of this study were published in Nature Genetics.

CIRM-funded study helps unlock some of the genetic secrets behind macular degeneration

Retina affected by age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in people over 60. It affects 10 million Americans. That’s more than cataracts and glaucoma combined. The causes of AMD are not known but are believed to involve a mixture of hereditary and environmental factors. There is no treatment for it.

Now, in a CIRM-funded study, researchers at UC San Diego (UCSD) have used stem cells to help identify genetic elements that could provide some clues as to the cause, and maybe give some ideas on how to treat it.

Before we get into what the researchers did let’s take a look at what AMD does. At a basic level it attacks the retina, the thin layer of tissue that lines the back of the eye. The retina receives light, turns it into electrical signals and sends it to the brain which turns it into a visual image.

The disease destroys the macula, the part of the retina that controls our central vision. At first, sight becomes blurred or fuzzy but over time it progresses to the point where central vision is almost completely destroyed.

To try and understand why this happens the team at UCSD took skin samples from six people with AMD and, using the iPSC method, turned those cells into the kinds of cell found in the retina. Because these cells came from people who had AMD they now displayed the same characteristics as AMD-affected retinal cells. This allowed the researchers to create what is called a “disease-in-a-dish” model that allowed them to see, in real time, what is happening in AMD.

They were able to identify a genetic variant that reduces production of a protein called VEGFA, which is known to promote the growth of new blood vessels.

In a news release Kelly Frazer, director of the Institute for Genomic Medicine at UCSD and the lead author of the study, said the results were unexpected.

Kelly Frazer, PhD, UC San Diego

“We didn’t start with the VEGFA gene when we went looking for genetic causes of AMD. But we were surprised to find that with samples from just six people, this genetic variation clearly emerged as a causal factor.”

Frazer says this discovery, published in the journal Stem Cell Reports, could ultimately lead to new approaches to developing new treatments for AMD.

CIRM already funds one clinical trial-stage project targeting AMD.

Stories that caught our eye: SanBio’s Traumatic Brain Injury trial hits its target; A new approach to endometriosis; and a SCID kid celebrates Halloween in style

TBI

Traumatic brain injury: graphic courtesy Brainline.org

Hopeful signs for treating brain injuries

There are more than 200,000 cases of traumatic brain injury (TBI) in the US every year. The injuries can be devastating, resulting in everything from difficult sleeping to memory loss, depression and severe disability. There is no cure. But this week the SanBio Group had some encouraging news from its Phase 2 STEMTRA clinical trial.

In the trial patients with TBI were given stem cells, derived from the bone marrow of healthy adult donors. When transplanted into the area of injury in the brain, these cells appear to promote recovery by stimulating the brain’s own regenerative ability.

In this trial the cells demonstrated what the company describes as “a statistically significant improvement in their motor function compared to the control group.”

CIRM did not fund this research but we are partnering with SanBio on another clinical trial targeting stroke.

 

Using a woman’s own cells to heal endometriosis

Endometriosis is an often painful condition that is caused when the cells that normally line the inside of the uterus grow outside of it, causing scarring and damaging other tissues. Over time it can result in severe pain, infertility and increase a woman’s risk for ovarian cancer.

There is no effective long-term treatment but now researchers at Northwestern Medicine have developed an approach, using the woman’s own cells, that could help treat the problem.

The researchers took cells from women, turned them into iPS pluripotent stem cells and then converted those into healthy uterine cells. In laboratory tests these cells responded to the progesterone, the hormone that plays a critical role in the uterus.

In a news release, Dr. Serdar Bulun, a senior author of the study, says this opens the way to testing these cells in women:

“This is huge. We’ve opened the door to treating endometriosis. These women with endometriosis start suffering from the disease at a very early age, so we end up seeing young high school girls getting addicted to opioids, which totally destroys their academic potential and social lives.”

The study is published in the journal Stem Cell Reports.

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Happy Halloween from a scary SCID kid

A lot of the research we write about on the Stem Cellar focuses on potential treatments or new approaches that show promise. So every once in a while, it’s good to remind ourselves that there are already stem cell treatments that are not just showing promise, they are saving lives.

That is the case with Ja’Ceon Golden. Regular readers of our blog know that Ja’Ceon was diagnosed with Severe Combined Immunodeficiency (SCID) also known as “bubble baby disease” when he was just a few months old. Children born with SCID often die in the first few years of life because they don’t have a functioning immune system and so even a simple infection can prove life-threatening.

Fortunately Ja’Ceon was enrolled in a CIRM-funded clinical trial at UC San Francisco where his own blood stem cells were genetically modified to correct the problem.

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Today he is a healthy, happy, thriving young boy. These pictures, taken by his great aunt Dannie Hawkins, including one of him in his Halloween costume, show how quickly he is growing. And all thanks to some amazing researchers, an aunt who wouldn’t give up on him, and the support of CIRM.

New stem cell technique gives brain support cells a starring role

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The Salk team. From left: Krishna Vadodaria, Lynne Moore, Carol Marchetto, Arianna Mei, Fred H. Gage, Callie Fredlender, Ruth Keithley, Ana Diniz Mendes. Photo courtesy Salk Institute

Astrocytes are some of the most common cells in the brain and central nervous system but they often get overlooked because they play a supporting role to the more glamorous neurons (even though they outnumber them around 50 to 1). But a new way of growing those astrocytes outside the brain could help pave the way for improved treatments for stroke, Alzheimer’s and other neurological problems.

Astrocytes – which get their name because of their star shape (Astron – Greek for “star” and “kyttaron” meaning cell) – have a number of key functions in the brain. They provide physical and metabolic support for neurons; they help supply energy and fuel to neurons; and they help with detoxification and injury repair, particularly in terms of reducing inflammation.

Studying these astrocytes in the lab has not been easy, however, because existing methods of producing them have been slow, cumbersome and not altogether effective at replicating their many functions.

Finding a better way

Now a team at the Salk Institute, led by CIRM-funded Professor Fred “Rusty” Gage, has developed a way of using stem cells to create astrocytes that is faster and more effective.

Their work is published in the journal Stem Cell Reports. In a news release, Gage says this is an important discovery:

“This work represents a big leap forward in our ability to model neurological disorders in a dish. Because inflammation is the common denominator in many brain disorders, better understanding astrocytes and their interactions with other cell types in the brain could provide important clues into what goes wrong in disease.”

Stylized microscopy image of an astrocyte (red) and neuron (green). (Salk Institute)

In a step by step process the Salk team used a series of chemicals, called growth factors, to help coax stem cells into becoming, first, generic brain cells, and ultimately astrocytes. These astrocytes not only behaved like the ones in our brain do, but they also have a particularly sensitive response to inflammation. This gives the team a powerful tool in helping develop new treatment to disorders of the brain.

But wait, there’s more!

As if that wasn’t enough, the researchers then used the same technique to create astrocytes from induced pluripotent stem cells (iPSCs) – adult cells, such as skin, that have been re-engineered to have the ability to turn into any other kind of cell in the body. Those man-made astrocytes also showed the same characteristics as natural ones do.

Krishna Vadodaria, one of the lead authors on the paper, says having these iPSC-created astrocytes gives them a completely new tool to help explore brain development and disease, and hopefully develop new treatments for those diseases.

“The exciting thing about using iPSCs is that if we get tissue samples from people with diseases like multiple sclerosis, Alzheimer’s or depression, we will be able to study how their astrocytes behave, and how they interact with neurons.”

A call to put the ‘public’ back in publication, and make stem cell research findings available to everyone

Opening the door

Opening the door to scientific knowledge

Thomas Gray probably wasn’t thinking about stem cell research when, in 1750 in his poem “Elegy in a Country Churchyard”, he wrote: “Full many a flower is born to blush unseen”. But a new study says that’s precisely what seems to happen to the findings of many stem cell clinical trials. They take place, but no details of their findings are ever made public. They blush, if they blush at all, unseen.

The study, in the journal Stem Cell Reports, says that only around 45 percent of stem cell clinical trials ever have their results published in peer-reviewed journals. Which means the results of around 55 percent of stem cell clinical trials are never shared with either the public or the scientific community.

Now, this finding apparently is not confined to stem cell research. Previous studies have shown a similar lack of publication of the results of more conventional therapies. Nonetheless, it’s a little disappointing – to say the least – to find out that so much knowledge and potentially valuable data is being lost due to lack of publication.

Definitely not full disclosure

Researchers at the University of Alberta in Canada used the US National Institute of Health’s (NIH) clinicaltrials.gov website as their starting point. They identified 1,052 stem cell clinical trials on the site. Only 393 trials were completed and of these, just 179 (45.4 percent) published their findings in a peer-reviewed journal.

In an interview in The Scientist, Tania Bubela, the lead researcher, says they chose to focus on stem cell clinical trials because of extensive media interest and the high public expectations for the field:

“When you have a field that is accused of over promising in some areas, it is beholden of the researchers in that field to publish the results of their trials so that the public and policy makers can realistically estimate the potential benefits.”

Now, it could be argued that publishing in a peer-reviewed journal is a rather high bar, that many researchers may have submitted articles but were rejected. However, there are other avenues for researchers to publish their findings, such as posting results on the clinicaltrials.gov database. Only 37 teams (3.5 percent) did that.

Why do it?

In the same article in The Scientist, Leigh Turner, a bioethicist at the University of Minnesota, raises the obvious question:

“The study shows a gap between studies that have taken place and actual publication of the data, so a substantial number of trials testing cell-based interventions are not entering the public domain. The underlying question is, what is the ethical and scientific basis to exposing human research subjects to risk if there is not going to be any meaningful contribution to knowledge at the end of the process?”

In short, why do it if you are not going to let anyone know what you did and what you found?

It’s a particularly relevant question when you consider that much of this research was supported with taxpayer dollars from the NIH and other institutions. So, if the public is paying for this research, doesn’t the public have a right to know what was learned?

Right to know

At CIRM we certainly think so. We expect and encourage all the researchers we fund to publish their findings. There are numerous ways and places to do that. For example, we expect each grantee to post a lay summary of their progress which we publish on our website. Stanford’s Dr. Joseph Wu’s progress reports for his work on heart disease shows you what those look like.

We also require researchers conducting clinical trials that we are funding to submit and post their trial results on the clinicaltrials.gov website.

The International Society for Stem Cell Research (ISSCR), agrees and recently updated its Guidelines for Stem Cell Research and Clinical Translation calling on researchers to publish, as fully as possible, their clinical trial results.

That is true regardless of whether or not the clinical trial showed it was both safe and effective, or whether it showed it was unsafe and ineffective. We can learn as much from failure as we can from success. But to do that we need to know what the results are.

Publishing only positive findings skews the scientific literature, and public perception of this work. Ignoring the negative could mean that other scientists waste a lot of time and money trying to do something that has already demonstrated it won’t work.

Publication should be a requirement for all research, particularly publicly funded research. It’s time to put the word “public” back in publication.

 

 

New stem cell could offer new ways to study birth defects

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Tony Parenti, MSU Ph.D student in cell and molecular biology

You never know what you are going to find in the trash. For a group of intrepid researchers at Michigan State University their discovery could lead to new ways of studying birth defects and other reproductive problems. Because what they found in what’s normally considered cellular trash was a new kind of stem cell.

The cell is called an induced extraembryonic endoderm stem (iXEN) cell. The team’s findings are reported in the journal Stem Cell Reports and here’s how lead author Tony Parenti described what they found:

“Other scientists may have seen these cells before, but they were considered to be defective, or cancer-like. Rather than ignore these cells that have been mislabeled as waste byproducts, we found gold in the garbage.”

Here’s the backstory to this discovery. For years researchers have considered embryonic stem cells as the “gold standard” for pluripotent cells, the kind that can be differentiated, or changed, into all kinds of cell in the body.

But studies in mice show that in addition to creating these pluripotent stem cells, the mouse embryo also produces extraembryonic endoderm or XEN cells. For a long time it was believed the gene expression of XEN cells affected the pluripotent stem cells, but the XEN cells were usually thought to be cancer-like, something that occurred as a byproduct of the developing embryo.

Searching through the trash

And that’s how things stayed until the research team at MSU noticed a bunch of XEN-like cells showing up every time they created induced pluripotent stem (iPS) cells – a kind of man-made equivalent of embryonic cells with the ability to turn into any other kind of cell but derived in a different way, reprogrammed from adult cells.

So they set out to see how important these, what they called induced or iXEN, cells were to the development of iPS cells. The researchers took  adult mouse cells and reprogrammed them into iPS cells and noticed colonies of iXEN cells in these cultures.

The first goal was to make sure these iXEN cells weren’t cancer-causing, as many researchers believed. This took six months but at the end of it not only were they able to demonstrate that the cells aren’t cancer-causing in a cell culture dish, but that they are a new type of stem cell.

Next step was to see how important endodermal genes are in the formation of iXEN cells. They found that decreasing endodermal gene expression led to a two-fold decrease in the number of iXEN cells and a significant increase in the number of iPS cells.

Competitors not collaborators

They concluded that the parallel pathways that generate pluripotent and XEN cells are in competition with each other and not in support of each other during reprogramming. By suppressing one they were able to boost the other. To their delight they had stumbled on a more efficient way of creating iPS cells.

While the discovery of a new kind of stem cell is always exciting there’s a catch to this; we still don’t know if XEN cells are found in humans. But this discovery gives the researchers additional tools to try and find the answer to that question.

Amy Ralston, a co-author of the study, said in a news release:

“It’s a missing tool that we don’t have yet. It’s true that XEN cells have characteristics that pluripotent stem cells do not have. Because of those traits, iXEN cells can shed light on reproductive diseases. If we can continue to unlock the secrets of iXEN cells, we may be able to improve induced pluripotent stem cell quality and lay the groundwork for future research on tissues that protect and nourish the human embryo.”

Normally the discovery of anything new, particularly when it over turns a long-held belief, is met with a degree of healthy skepticism at first. In science that’s a good thing. We all remember the eager way that STAP stem cells were hailed by many as a new way to create pluripotent stem cells until the research was discredited. But so far the Twitterverse and media outlets seems to share in the excitement about this discovery.

Regenerating damaged muscle after a heart attack

Cardio cells image

Images of clusters of heart muscle cells (in red and green) derived from human embryonic stem cells 40 days after transplantation. Courtesy UCLA

Every year more than 735,000 Americans have a heart attack. Many of those who survive often have lasting damage to their heart muscle and are at increased risk for future attacks and heart failure. Now CIRM-funded researchers at UCLA have identified a way that could help regenerate heart muscle after a heart attack, potentially not only saving lives but also increasing the quality of life.

The researchers used human embryonic stem cells to create a kind of cell, called a cardiac mesoderm cell, which has the ability to turn into cardiomyocytes, fibroblasts, smooth muscle, and endothelial cells. All these types of cells play an important role in helping repair a damaged heart.

As those embryonic cells were in the process of changing into cardiac mesoderms, the team was able to identify two key markers on the cell surface. The markers, called CD13 and ROR2 – which makes them sound like extras in the latest Star Wars movie – pinpointed the cells that were likely to be the most efficient at changing into the kind of cells needed to repair damaged heart tissue.

The researchers then transplanted those cells into an animal model and found that not only did many of the cells survive but they also produced the cells needed to regenerate heart muscle and vessels.

Big step forward

The research was published in the journal Stem Cell Reports. Dr. Reza Ardehali, the senior author of the CIRM-funded study, says this is a big step forward in the use of embryonic stem cells to help treat heart attacks:

“In a major heart attack, a person loses an estimated 1 billion heart cells, which results in permanent scar tissue in the heart muscle. Our findings seek to unlock some of the mysteries of heart regeneration in order to move the possibility of cardiovascular cell therapies forward. We have now found a way to identify the right type of stem cells that create heart cells that successfully engraft when transplanted and generate muscle tissue in the heart, which means we’re one step closer to developing cell-based therapies for people living with heart disease.”

More good news

But wait, as they say in cheesy TV infomercials, there’s more. Ardehali and his team not only found the markers to help them identify the right kinds of cell to use in regenerating damaged heart muscle, they also found a way to track the transplanted cells so they could make sure they were going where they wanted them to, and doing what they needed them to.

In a study published in Stem Cells Translational Medicine,  Ardehali and his team used special particles that can be tracked using MRI. They used those particles to label the cardiac mesoderm cells. Once transplanted into the animal model the team was able to follow the cells for up to 40 days.

Ardehali says knowing how to identify the best cells to repair a damaged heart, and then being able to track them over a long period, gives us valuable tools to use as we work to develop better, more effective treatments for people who have had a heart attack.

CIRM is already funding a Phase 2 clinical trial, run by a company called Capricor, using stem cells to treat heart attack patients.