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.

Engineered T cells made from stem cells could provide immunity against multiple cancers

Dr. Lily Yang

Within all of our bodies there is a special type of “super” immune cell that holds enormous potential. Unlike regular immune cells that can only attack one cancer at a time, these “super” immune cells have the ability to target many types of cancers at once. These specialized cells are known as invariant natural killer T cells or iNKT cells for short. Unfortunately, there are relatively few of these cells normally present in the body.

However, in a CIRM-funded study, Dr. Lily Yang and her team of researchers at UCLA have found a way to produce iNKT cells from human blood stem cells. They were then able to test these iNKT cells on mice with both human bone marrow and human cancers. These mice either had multiple melanoma, a type of blood cancer, or melanoma, a solid tumor cancer. The researchers then studied what happened to mice’s immune system, cancers, and engineered iNKT cells after they had integrated into the bone marrow.

The results were remarkable. The team found that the blood stem cells now differentiated normally into iNKT cells, producing iNKT cells for the rest of the animal’s life, which was generally about a year. Mice without the engineered stem cell transplants had undetectable levels of iNKT cells while those that received the engineered cells had iNKT cells make up as much as 60% of the total immune system cells. The team also found that the engineered iNKT cells were able to suppress tumor growth in both multiple myeloma and melanoma.

Dr. Yang, in a press release by UCLA health, discussed the significance of the results in this animal model and the enormous potential this could have for cancer patients.

“What’s really exciting is that we can give this treatment just once and it increases the number of iNKT cells to levels that can fight cancer for the lifetime of the animals.” said Yang.

In the same press release, Dr. Yang continued to highlight the study’s importance by saying that,

“One advantage of this approach is that it’s a one-time cell therapy that can provide patients with a lifelong supply of iNKT cells.”

Researchers mentioned that they could control total iNKT cell make up in the immune system depending on how they engineered the blood stem cells. However, more research is needed to determine how these engineered iNKT cells might be useful for treating cancer in humans and evaluating any long-term side effects associated with an increased number of these cells.

The full results of this study were published in the journal Cell Stem Cell.

“Brains” in a dish that can create electrical impulses

Brain organoids in a petri dish: photo courtesy UCSD

For several years, researchers have been able to take stem cells and use them to make three dimensional structures called organoids. These are a kind of mini organ that scientists can then use to study what happens in the real thing. For example, creating kidney organoids to see how kidney disease develops in patients.

Scientists can do the same with brain cells, creating clumps of cells that become a kind of miniature version of parts of the brain. These organoids can’t do any of the complex things our brains do – such as thinking – but they do serve as useful physical models for us to use in trying to develop a deeper understanding of the brain.

Now Alysson Muotri and his team at UC San Diego – in a study supported by two grants from CIRM – have taken the science one step further, developing brain organoids that allow us to measure the level of electrical activity they generate, and then compare it to the electrical activity seen in the developing brain of a fetus. That last sentence might cause some people to say “What?”, but this is actually really cool science that could help us gain a deeper understanding of how brains develop and come up with new ways to treat problems in the brain caused by faulty circuitry, such as autism or schizophrenia.

The team developed new, more effective methods of growing clusters of the different kinds of cells found in the brain. They then placed them on a multi-electrode array, a kind of muffin tray that could measure electrical impulses. As they fed the cells and increased the number of cells in the trays they were able to measure changes in the electrical impulses they gave off. The cells went from producing 3,000 spikes a minute to 300,000 spikes a minute. This is the first time this level of activity has been achieved in a cell-based laboratory model. But that’s not all.

When they further analyzed the activity of the organoids, they found there were some similarities to the activity seen in the brains of premature babies. For instance, both produced short bursts of activity, followed by a period of inactivity.

Alysson Muotri

In a news release Muotri says they were surprised by the finding:

“We couldn’t believe it at first — we thought our electrodes were malfunctioning. Because the data were so striking, I think many people were kind of skeptical about it, and understandably so.”

Muotri knows that this research – published in the journal Cell Stem Cell – raises ethical issues and he is quick to say that these organoids are nothing like a baby’s brain, that they differ in several critical ways. The organoids are tiny, not just in size but also in the numbers of cells involved. They also don’t have blood vessels to keep them alive or help them grow and they don’t have any ability to think.

“They are far from being functionally equivalent to a full cortex, even in a baby. In fact, we don’t yet have a way to even measure consciousness or sentience.”

What these organoids do have is the ability to help us look at the structure and activity of the brain in ways we never could before. In the past researchers depended on mice or other animals to test new ideas or therapies for human diseases or disorders. Because our brains are so different than animal brains those approaches have had limited results. Just think about how many treatments for Alzheimer’s looked promising in animal models but failed completely in people.

These new organoids allow us to explore how new therapies might work in the human brain, and hopefully increase our ability to develop more effective treatments for conditions as varied as epilepsy and autism.

Boosting the blood system after life-saving therapy

Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right): Photo Courtesy UCLA

Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.

First a little background. Some cancer treatments use chemotherapy and radiation to kill the cancer, but they can also damage other cells, including those in the bone marrow responsible for making blood stem cells. Those cells eventually recover but it can take weeks or months, and during that time the patient may feel fatigue and be more susceptible to infections and other problems.

In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.

They focused their attention on a protein called PTP-sigma that is found in blood stem cells and acts as a kind of brake on the regeneration of those cells. Previous studies by Dr. Chute showed that, after undergoing radiation, mice that have less PTP-sigma were able to regenerate their blood stem cells faster than mice that had normal levels of the protein.

John Chute: Photo courtesy UCLA

So they set out to identify something that could help reduce levels of PTP-sigma without affecting other cells. They first identified an organic compound with the charming name of 6545075 (Chembridge) that was reported to be effective against PTP-sigma. Then they searched a library of 80,000 different small molecules to find something similar to 6545075 (and this is why science takes so long).

From that group they developed more than 100 different drug candidates to see which, if any, were effective against PTP-sigma. Finally, they found a promising candidate, called DJ009. In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in human blood stem cells.

They then tested DJ009 in mice that were given high doses of radiation. In a news release Dr. Chute said the results were very encouraging:

“The potency of this compound in animal models was very high. It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”

Of the radiated mice, most that were given DJ009 survived. In comparison, those that didn’t get DJ009 died within three weeks.

They saw similar benefits in mice given chemotherapy. Mice with DJ009 saw their white blood cells – key components of the immune system – return to normal within two weeks. The untreated mice had dangerously low levels of those cells at the same point.

It’s encouraging work and the team are already getting ready for more research so they can validate their findings and hopefully take the next step towards testing this in people in clinical trials.

Drug used to treat multiple sclerosis may improve glioblastoma outcomes

Dr. Jeremy Rich, UC San Diego

Glioblastoma is an aggressive form of cancer that invades brain tissue, making it extremely difficult to treat. Current therapies involving radiation and chemotherapy are effective in destroying the bulk of brain cancer cells, but they are not able to reach the brain cancer stem cells, which have the ability to grow and multiply indefinitely. These cancer stem cells enable the glioblastoma to continuously grow even after treatment, which leads to recurring tumor formation.

Dr. Jeremy Rich and his team at UC San Diego examined glioblastomas further by obtaining glioblastoma tumor samples donated by patients that underwent surgery and implanting these into mice. Dr. Rich and his team tested a combinational treatment that included a targeted cancer therapy alongside a drug named teriflunomide, which is used to treatment patients with multiple sclerosis. The research team found that this approach successfully halted the growth of glioblastoma stem cells, shrank the tumor size, and improved survival in the mice.

In order to continue replicating, glioblastoma stem cells make pyrimidine, one of the compounds that make up DNA. Dr. Rich and his team noticed that higher rates of pyrimidine were associated with poor survival rates in glioblastoma patients. Teriflunomide works by blocking an enzyme that is necessary to make pyrmidine, therefore inhibiting glioblastoma stem cell replication.

In a press release, Dr. Rich talks about the potential these findings hold by stating that,

“We’re excited about these results, especially because we’re talking about a drug that’s already known to be safe in humans.”

However, he comments on the need to evaluate this approach further by saying that,

“This laboratory model isn’t perfect — yes it uses human patient samples, yet it still lacks the context a glioblastoma would have in the human body, such as interaction with the immune system, which we know plays an important role in determining tumor growth and survival. Before this drug could become available to patients with glioblastoma, human clinical trials would be necessary to support its safety and efficacy.”

The full results to this study were published in Science Translational Medicine.

Stem cell progress and promise in fighting leukemia

Computer illustration of a cancerous white blood cell in leukemia.

There is nothing you can do to prevent or reduce your risk of leukemia. That’s not a very reassuring statement considering that this year alone almost 62,000 Americans will be diagnosed with leukemia; almost 23,000 will die from the disease. That’s why CIRM is funding four clinical trials targeting leukemia, hoping to develop new approaches to treat, and even cure it.

That’s also why our next special Facebook Live “Ask the Stem Cell Team” event is focused on this issue. Join us on Thursday, August 29th from 1pm to 2pm PDT to hear a discussion about the progress in, and promise of, stem cell research for leukemia.

We have two great panelists joining us:

Dr. Crystal Mackall, has many titles including serving as the Founding Director of the Stanford Center for Cancer Cell Therapy.  She is using an innovative approach called a Chimeric Antigen Receptor (CAR) T Cell Therapy. This works by isolating a patient’s own T cells (a type of immune cell) and then genetically engineering them to recognize a protein on the surface of cancer cells, triggering their destruction. This is now being tested in a clinical trial funded by CIRM.

Natasha Fooman. To describe Natasha as a patient advocate would not do justice to her experience and expertise in fighting blood cancer and advocating on behalf of those battling the disease. For her work she has twice been named “Woman of the Year” by the Leukemia and Lymphoma Society. In 2011 she was diagnosed with a form of lymphoma that was affecting her brain. Over the years, she would battle lymphoma three times and undergo chemotherapy, radiation and eventually a bone marrow transplant. Today she is cancer free and is a key part of a CIRM team fighting blood cancer.

We hope you’ll join us to learn about the progress being made using stem cells to combat blood cancers, the challenges ahead but also the promising signs that we are advancing the field.

We also hope you’ll take an active role by posting questions on Facebook during the event, or sending us questions ahead of time to info@cirm.ca.gov. We will do our best to address as many as we can.

Here’s the link to the event, feel free to share this with anyone you think might be interested in joining us for Facebook Live “Ask the Stem Cell Team about Leukemia”

CIRM-Funded Researchers Develop Chimeric “Mighty Mouse” Model to Study Alzheimer’s Disease

Dr. Mathew Blurton-Jones, leader of team that developed the chimeric “Mighty Mouse” model at the University of California, Irvine

In ancient Greek mythology, a Chimera was a creature that was usually depicted as a lion with an additional goat head and a serpent for a tail. Due to the Chimera’s animal hybrid nature, the term “chimeric” came to fruition in the scientific community as a way to describe an organism containing two or more different sets of DNA.

A CIRM-funded study conducted by Dr. Mathew Blurton-Jones and his team at UC Irvine describes a way for human brain immune cells, known as microglia, to grow and function inside mice. Since the mice contain a both human cells and their own mice cells, they are described as being chimeric.

In order to develop this chimeric “mighty mouse” model, Dr. Blurton-Jones and his team generated induced pluripotent stem cells (iPSCs), which have the ability to turn into any kind of cell, from cell samples donated by adult patients. For this study, the researchers converted iPSCs into microglia, a type of immune cell found in the brain, and implanted them into genetically modified mice. After a few months, they found that the implanted cells successfully integrated inside the brains of the mice.

By finding a way to look at human microglia grow and function in real time in an animal model, scientists can further analyze crucial mechanisms contributing to neurological conditions such as Alzheimer’s, Parkinson’s, traumatic brain injury, and stroke.

For this particular study, Dr. Blurton-Jones and his team looked at human microglia in the mouse brain in relation to Alzheimer’s, which could hold clues to better understand and treat the disease. The team did this by introducing amyloid plaques, protein fragments in the brain that accumulate in people with Alzheimer’s, and evaluating how the human microglia responded. They found that the human microglia migrated toward the amyloid plaques and surrounding them, which is what is observed in Alzheimer’s patients.

In a press release, Dr. Blurton-Jones expressed the importance of studying microglia by stating that,

“Microglia are now seen as having a crucial role in the development and progression of Alzheimer’s. The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer’s and the majority of these are switched on in microglia. However, so far we’ve only been able to study human microglia at the end stage of Alzheimer’s in post-mortem tissues or in petri dishes.”

Furthermore, Dr. Blurton-Jones highlighted the importance of looking at human microglia in particular by saying that,

“The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cell.”

The full results of this study were published in Cell.

One family’s fight to save their son’s life, and how stem cells made it possible

CIRM’s mission is very simple: to accelerate stem cell treatments to patients with unmet medical needs. Anne Klein’s son, Everett, was a poster boy for that statement. Born with a fatal immune disorder Everett faced a bleak future. But Anne and husband Brian were not about to give up. The following story is one Anne wrote for Parents magazine. It’s testament to the power of stem cells to save lives, but even more importantly to the power of love and the determination of a family to save their son.

My Son Was Born With ‘Bubble Boy’ Disease—But A Gene Therapy Trial Saved His Life

Everett Schmitt. Photo: Meg Kumin

I wish more than anything that my son Everett had not been born with severe combined immunodeficiency (SCID). But I know he is actually one of the lucky unlucky ones. By Anne Klein

As a child in the ’80s, I watched a news story about David Vetter. David was known as “the boy in the bubble” because he was born with severe combined immunodeficiency (SCID), a rare genetic disease that leaves babies with very little or no immune system. To protect him, David lived his entire life in a plastic bubble that kept him separated from a world filled with germs and illnesses that would have taken his life—likely before his first birthday.

I was struck by David’s story. It was heartbreaking and seemed so otherworldly. What would it be like to spend your childhood in an isolation chamber with family, doctors, reporters, and the world looking in on you? I found it devastating that an experimental bone marrow transplant didn’t end up saving his life; instead it led to fatal complications. His mother, Carol Ann Demaret, touched his bare hand for the first and last time when he was 12 years old.

I couldn’t have known that almost 30 years later, my own son, Everett, would be born with SCID too.

Everett’s SCID diagnosis

At birth, Everett was big, beautiful, and looked perfectly healthy. My husband Brian and I already had a 2-and-a-half-year-old son, Alden, so we were less anxious as parents when we brought Everett home. I didn’t run errands with Alden until he was at least a month old, but Everett was out and about with us within a few days of being born. After all, we thought we knew what to expect.

But two weeks after Everett’s birth, a doctor called to discuss Everett’s newborn screening test results. I listened in disbelief as he explained that Everett’s blood sample indicated he may have an immune deficiency.

“He may need a bone marrow transplant,” the doctor told me.

I was shocked. Everett’s checkup with his pediatrician just two days earlier went swimmingly. I hung up and held on to the doctor’s assurance that there was a 40 percent chance Everett’s test result was a false positive.

After five grueling days of waiting for additional test results and answers, I received the call: Everett had virtually no immune system. He needed to be quickly admitted to UCSF Benioff Children’s Hospital in California so they could keep him isolated and prepare to give him a stem cell transplant. UCSF diagnosed him specifically with SCID-X1, the same form David battled.

Beginning SCID treatment

The hospital was 90 miles and more than two hours away from home. Our family of four had to be split into two, with me staying in the hospital primarily with Everett and Brian and Alden remaining at home, except for short visits. The sudden upheaval left Alden confused, shaken, and sad. Brian and I quickly transformed into helicopter parents, neurotically focused on every imaginable contact with germs, even the mildest of which could be life-threatening to Everett.

When he was 7 weeks old, Everett received a stem cell transplant with me as his donor, but the transplant failed because my immune cells began attacking his body. Over his short life, Everett has also spent more than six months collectively in the hospital and more than three years in semi-isolation at home. He’s endured countless biopsies, ultrasounds, CT scans, infusions, blood draws, trips to the emergency department, and medical transports via ambulance or helicopter.

Gene therapy to treat SCID

At age 2, his liver almost failed and a case of pneumonia required breathing support with sedation. That’s when a doctor came into the pediatric intensive care unit and said, “When Everett gets through this, we need to do something else for him.” He recommended a gene therapy clinical trial at the National Institutes of Health (NIH) that was finally showing success in patients over age 2 whose transplants had failed. This was the first group of SCID-X1 patients to receive gene therapy using a lentiviral vector combined with a light dose of chemotherapy.

After the complications from our son’s initial stem cell transplant, Brian and I didn’t want to do another stem cell transplant using donor cells. My donor cells were at war with his body and cells from another donor could do the same. Also, the odds of Everett having a suitable donor on the bone marrow registry were extremely small since he didn’t have one as a newborn. At the NIH, he would receive a transplant with his own, perfectly matched, gene-corrected cells. They would be right at home.

Other treatment options would likely only partially restore his immunity and require him to receive infusions of donor antibodies for life, as was the case with his first transplant. Prior gene therapy trials produced similarly incomplete results and several participants developed leukemia. The NIH trial was the first one showing promise in fully restoring immunity, without a risk of cancer. Brian and I felt it was Everett’s best option. Without hesitation, we flew across the country for his treatment. Everett received the gene therapy in September 2016 when he was 3, becoming the youngest patient NIH’s clinical trial has treated.

Everett’s recovery

It’s been more than two years since Everett received gene therapy and now more than ever, he has the best hope of developing a fully functioning immune system. He just received his first vaccine to test his ability to mount a response. Now 6 years old, he’s completed kindergarten and has been to Disney World. He plays in the dirt and loves shows and movies from the ’80s (maybe some of the same ones David enjoyed).

Everett knows he has been through a lot and that his doctors “fixed his DNA,” but he’s focused largely on other things. He’s vocal when confronted with medical pain or trauma, but seems to block out the experiences shortly afterwards. It’s sad for Brian and me that Everett developed these coping skills at such a young age, but we’re so grateful he is otherwise expressive and enjoys engaging with others. Once in the middle of the night, he woke us up as he stood in the hallway, exclaiming, “I’m going back to bed, but I just want you to know that I love you with all my heart!”

I wish more than anything that Everett had not been born with such a terrible disease and I could erase all the trauma, isolation, and pain. But I know that he is actually one of the lucky unlucky ones. Everett is fortunate his disease was caught early by SCID newborn screening, which became available in California not long before his birth. Without this test, we would not have known he had SCID until he became dangerously ill. His prognosis would have been much worse, even under the care of his truly brilliant and remarkable doctors, some of whom cared for David decades earlier.

Carol-Ann-mother-of-David-Vetter-meeting-Everett-Schmitt
Everett Schmitt meeting David Vetter’s mom Carol Ann Demaret. Photo – Brian Schmitt

When Everett was 4, soon after the gene therapy gave him the immunity he desperately needed, our family was fortunate enough to cross paths with David’s mom, Carol Ann, at an Immune Deficiency Foundation event. Throughout my life, I had seen her in pictures and on television with David. In person, she was warm, gracious, and humble. When I introduced her to Everett and explained that he had SCID just like David, she looked at Everett with loving eyes and asked if she could touch him. As she touched Everett’s shoulder and they locked eyes, Brian and I looked on with profound gratitude.

Anne Klein is a parent, scientist, and a patient advocate for two gene therapy trials funded by the California Institute for Regenerative Medicine. She is passionate about helping parents of children with SCID navigate treatment options for their child.

You can read about the clinical trials we are funding for SCID here, here, here and here.

How stem cells know the right way to make a heart . And what goes wrong when they don’t

Gladstone scientists Deepak Srivastava (left), Yvanka De Soysa (center), and Casey Gifford (right) publish a complete catalog of the cells involved in heart development.

The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.

In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.

In a story in Science and Research Technology News, Casey Gifford, a senior author on the study, said this approach helps pinpoint genetic variants that might be causing problems.

“This sequencing technique allowed us to see all the different types of cells present at various stages of heart development and helped us identify which genes are activated and suppressed along the way. We were not only able to uncover the existence of unknown cell types, but we also gained a better understanding of the function and behavior of individual cells—information we could never access before.”

Then they partnered with a team at Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg which ran a computational analysis to identify which genes were involved in creating different cell types. This highlighted one specific gene, called Hand2, that controls the activity of thousands of other genes. They found that a lack of Hand2 in mice led to an inability to form one of the heart’s chambers, which in turn led to impaired blood flow to the lungs. The embryo was creating the cells needed to form the chamber, but not a critical pathway that would allow those cells to get where they were needed when they were needed.

Gifford says this has given us a deeper insight into how cells are formed, knowledge we didn’t have before.

“Single-cell technologies can inform us about how organs form in ways we couldn’t understand before and can provide the underlying cause of disease associated with genetic variations. We revealed subtle differences in very, very small subsets of cells that actually have catastrophic consequences and could easily have been overlooked in the past. This is the first step toward devising new therapies.”

These therapies are needed to help treat congenital heart defects, which are the most common and deadly birth defects. There are more than 2.5 million Americans with these defects. Deepak Srivastava, President of Gladstone and the leader of the study, said the knowledge gained in this study could help developed strategies to help address that.

“We’re beginning to see the long-term consequences in adults, and right now, we don’t really have any way to treat them. My hope is that if we can understand the genetic causes and the cell types affected, we could potentially intervene soon after birth to prevent the worsening of their state over time.

The study is published in the journal Nature.

CIRM Board Approves $19.7 Million in Awards for Translational Research Program

In addition to approving funding for breast cancer related brain metastases last week, the CIRM Board also approved an additional $19.7 million geared towards our translational research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.

Before getting into the details of each project, here is a table with a brief synopsis of the awards:

TRAN1 – 11532

Illustration of a healthy eye vs eye with AMD

$3.73 million was awarded to Dr. Mark Humayun at USC to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD).

AMD is an eye disease that causes severe vision impairment, resulting in the inability to read, drive, recognize faces, and blindness if left untreated.  It is the leading cause of vision loss in the U.S. and currently affects over 2 million Americans.  By the year 2050, it is projected that the number of affected individuals will more than double to over 5 million.  A layer of cells in the back of the eye called the retinal pigment epithelium (RPE) provide support to photoreceptors (PRs), specialized cells that play an important role in our ability to process images.  The dysfunction and/or loss of RPE cells plays a critical role in the loss of PRs and hence the vision problems observed in AMD.  One form of AMD is known as dry AMD (dAMD) and accounts for about 90% of all AMD cases.

The approach that Dr. Humayun is developing will use a biologic product produced by human embryonic stem cells (hESCs). This material will be injected into the eye of patients with early development of dAMD, supporting the survival of photoreceptors in the affected retina.

TRAN1 – 11579

Illustration depicting the role neuronal relays play in muscle sensation

$6.23 million was awarded to Dr. Mark Tuszynski at UCSD to develop a neural stem cell therapy for spinal cord injury (SCI).

According to data from the National Spinal Cord Injury Statistical Center, as of 2018, SCI affects an estimated 288,000 people in the United States alone, with about 17,700 new cases each year. There are currently no effective therapies for SCI. Many people suffer SCI in early adulthood, leading to life-long disability and suffering, extensive treatment needs and extremely high lifetime costs of health care.

The approach that Dr. Tuszynski is developing will use hESCs to create neural stem cells (NSCs).  These newly created NSCs would then be grafted at the site of injury of those with SCI.  In preclinical studies, the NSCs have been shown to support the formation of neuronal relays at the site of SCI.  The neuronal relays allow the sensory neurons in the brain to communicate with the motor neurons in the spinal cord to re-establish muscle control and movement.

TRAN1 – 11548

Graphic depicting the challenges of traumatic brain injury (TBI)

$4.83 million was awarded to Dr. Brian Cummings at UC Irvine to develop a neural stem cell therapy for traumatic brain injury (TBI).

TBI is caused by a bump, blow, or jolt to the head that disrupts the normal function of the brain, resulting in emotional, mental, movement, and memory problems. There are 1.7 million people in the United States experiencing a TBI that leads to hospitalization each year. Since there are no effective treatments, TBI is one of the most critical unmet medical needs based on the total number of those affected and on a cost basis.

The approach that Dr. Cummings is developing will also use hESCs to create NSCs.  These newly created NSCs would be integrated with injured tissue in patients and have the ability to turn into the three main cell types in the brain; neurons, astrocytes, and oligodendrocytes.  This would allow for TBI patients to potentially see improvements in issues related to memory, movement, and anxiety, increasing independence and lessening patient care needs.

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Illustration depicting the brain damage that occurs under hypoxic-ischemic conditions

$4.96 million was awarded to Dr. Evan Snyder at Sanford Burnham Prebys to develop a neural stem cell therapy for perinatal hypoxic-ischemic brain injury (HII).

HII occurs when there is a lack of oxygen flow to the brain.  A newborn infant’s body can compensate for brief periods of depleted oxygen, but if this lasts too long, brain tissue is destroyed, which can cause many issues such as developmental delay and motor impairment.  Current treatment for this condition is whole-body hypothermia (HT), which consists of significantly reducing body temperature to interrupt brain injury.  However, this is not very effective in severe cases of HII. 

The approach that Dr. Snyder is developing will use an established neural stem cell (NSC) line.   These NSCs would be injected and potentially used alongside HT treatment to increase protection from brain injury.