Two rare diseases, two pieces of good news

Dr. Stephanie Cherqui

Last week saw a flurry of really encouraging reports from projects that CIRM has supported. We blogged about two of them last Wednesday, but here’s another two programs showing promising results.

UC San Diego researcher Dr. Stephanie Cherqui is running a CIRM-funded clinical trial for cystinosis. This is a condition where patients lack the ability to clear an amino acid called cystine from their cells. As the cystine builds up it can lead to multi-organ failure affecting the kidneys, eyes, thyroid, muscle, and pancreas.

Dr. Cherqui uses the patient’s own blood stem cells, that have been genetically corrected in the lab to remove the defective gene that causes the problem. It’s hoped these new cells will help reduce the cystine buildup.

The data presented at the annual meeting of the American Society of Cell and Gene Therapy (ASCGT) focused on the first patient treated with this approach. Six months after being treated the patient is showing positive trends in kidney function. His glomerular filtration rate (a measure of how well the kidneys are working) has risen from 38 (considered a sign of moderate to severe loss of kidney function) to 52 (mild loss of kidney function). In addition, he has not had to take the medication he previously needed to control the disorder, nor has he experienced any serious side effects from the therapy.

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Dr. Linda Marban of Capricor

Capricor Therapeutics also had some positive news about its therapy for people with Duchenne’s Muscular Dystrophy (DMD). This is a progressive genetic disorder that slowly destroys the muscles. It affects mostly boys. By their teens many are unable to walk, and most die of heart or lung failure in their 20’s. 

Capricor is using a therapy called CAP-1002, using cells derived from heart stem cells, in the HOPE-2 clinical trial.

In a news release Capricor said 12-month data from the trial showed improvements in heart function, lung function and upper body strength. In contrast, a placebo control group that didn’t get the CAP-1002 treatment saw their condition deteriorate.

Craig McDonald, M.D., the lead investigator on the study, says these results are really encouraging.  “I am incredibly pleased with the outcome of the HOPE-2 trial which demonstrated clinically relevant benefits of CAP-1002 which resulted in measurable improvements in upper limb, cardiac and respiratory function. This is the first clinical trial which shows benefit to patients in advanced stages of DMD for which treatment options are limited.”

You can read the story of Caleb Sizemore, one of the patients treated in the CIRM-funded portion of this trial.

Treatment for heart failure shows promising results for COVID-19 patients

Dr. Linda Marbán

To help with the coronavirus pandemic, many scientists are repurposing previously developed approaches or treatments to see if they can be used to treat patients with COVID-19. Capricor Therapeutics, lead by Dr. Linda Marbán, is using cardiosphere derived cells (CDCs), which are stem cells derived from heart tissue, to treat critically ill patients with COVID-19.

When a patient contracts the virus, their body produces cytokines, proteins that play an important role in the immune response. Unfortunately, having too many cytokines, known as a “cytokine storm”, leads to a severe immune reaction that can cause pneumonia, organ failure, and death. CDCs in previous studies have been shown to help regulate the immune response and cytokines, which could help patients with COVID-19.

Over the course of one month, six critically ill patients with COVID-19, five of whom were on mechanical ventilators, were treated with CDCs. In these compassionate care cases, five male patients and one female patient received treatment. Of the five patients on ventilator support, four patients no longer required ventilator support within just one to four days after treatment. Although these results are promising, it is important to remember that this treatment is in very early testing and will need to demonstrate significant improvement in larger patient groups.

Following a review of the results of this small study, the U.S. Food and Drug Administration (FDA) approved treatment of up to an 20 additional COVID-19 patients.

In a press release, Dr. Marbán discuses the results of the compassionate care study and treatment of additional COVID-19 patients.

“As the global medical community continues to come together in its battle against COVID-19, the results of our initial compassionate care cases are extremely promising and what we had anticipated. We look forward to continuing to treat additional patients under our recently approved expanded access program Investigational New Drug application.” 

The treatment used was developed with the help of a CIRM funded preclinical study. It has also been used in three CIRM funded clinical trials for heart disease associated with duchenne muscular dystrophy, heart failure, and pulmonary arterial hypertension.

Encouraging Progress for Two CIRM Supported Clinical Trials

This past Wednesday was Stem Cell Awareness Day, a day that is meant to remind us all of the importance of stem cell research and the potential it has to treat a wide variety of diseases. On this day, we also released an independent Economic Impact Report that showed how $10.7 Billion (yes, you read that right) was generated as a direct result of the the legacy we have built as a state agency that funds groundbreaking research.

Aside from the monetary incentive, which is an added bonus, the research we fund has made encouraging progress in the scientific field and has demonstrated the positive impact it can have on various disease areas. This week, two clinical trials supported by CIRM funding have released very promising updates.

Duchenne Muscular Dystrophy

Capricor Therapeutics, Inc. has presented positive results for a clinical trial related to a treatment for duchenne muscular dystrophy (DMD), a genetic disorder. DMD leads to progressive muscle degeneration and weakness due to its effect on a protein called dystrophin, which helps keep muscle cells intact.

The treatment that Capricor is testing is called CAP-1002 and consists of a unique population of cells that contain cardiac progenitor cells, a type of stem cell, that help encourage the regeneration of cells. CIRM funded an earlier clinical trial for this treatment.

The early results of this current trial describe how teens and young men in the advanced stages of DMD saw improvements in skeletal, lung, and heart measurements after receiving multiple doses of the treatment.

In a news release, Dr. Linda Marban, Chief Executive Officer of Capricor, expresses optimism for this clinical trial by saying,

“We are very pleased that the interim analysis from this double-blind placebo-controlled study, has demonstrated meaningful improvements across three clinically relevant endpoints in older patients with limited remaining treatment options.”

In the same news release, Dr. Craig McDonald, the national principal investigator for the trial, echoes the same sentiment by stating,

“The results from this trial to date are very promising in that the cells appear to positively impact skeletal, pulmonary and cardiac assessments in older DMD patients who have few, if any, remaining treatment options. We are eager to meet with the FDA to discuss the next steps for this promising program.”

Mantle Cell Lymphoma

Additionally, Oncternal Therapeutics has decided, because of positive results, to open an expansion of its CIRM-funded clinical trial aimed at treating patients with mantle cell lymphoma (MCL). The treatment involves an antibody called cirmtuzumab, named after us, in combination with a drug called ibrutinib.

The preliminary results were from the first six patients with MCL that were treated in the trial. One patient with MCL, who had relapsed following an allogeneic stem cell transplant, experienced a confirmed complete response (CR) after three months of cirmtuzumab plus ibrutinib treatment. This complete response appears to be sustained and has been confirmed to be ongoing after completing 12 months of the combination treatment. A second confirmed complete response occurred in a patient who had progressive disease after failing several different chemotherapy regimens, bone marrow transplant and CAR-T therapy. 

In a news release, Dr. Hun Lee, an investigator in the trial, states that,

“It is encouraging to see that the drug has been well tolerated as well as the early signal of efficacy of cirmtuzumab with ibrutinib in MCL, particularly the rapid and durable complete responses of the heavily pre-treated patients after three months of therapy, which is an unusually fast response in this patient population.”

From bench to bedside: a Q&A with stem cell expert Jan Nolta

At CIRM we are privileged to work with many remarkable people who combine brilliance, compassion and commitment to their search for new therapies to help people in need. One of those who certainly fits that description is UC Davis’ Jan Nolta.

This week the UC Davis Newsroom posted a great interview with Jan. Rather than try and summarize what she says I thought it would be better to let her talk for herself.

Jan Nolta
Jan Nolta

Talking research, unscrupulous clinics, and sustaining the momentum

(SACRAMENTO) —

In 2007, Jan Nolta returned to Northern California from St. Louis to lead what was at the time UC Davis’ brand-new stem cell program. As director of the UC Davis Stem Cell Program and the Institute for Regenerative Cures, she has overseen the opening of the institute, more than $140 million in research grants, and dozens upon dozens of research studies. She recently sat down to answer some questions about regenerative medicine and all the work taking place at UC Davis Health.

Q: Turning stem cells into cures has been your mission and mantra since you founded the program. Can you give us some examples of the most promising research?

I am so excited about our research. We have about 20 different disease-focused teams. That includes physicians, nurses, health care staff, researchers and faculty members, all working to go from the laboratory bench to patient’s bedside with therapies.

Perhaps the most promising and exciting research right now comes from combining blood-forming

stem cells with gene therapy. We’re working in about eight areas right now, and the first cure, something that we definitely can call a stem cell “cure,” is coming from this combined approach.

Soon, doctors will be able to prescribe this type of stem cell therapy. Patients will use their own bone marrow or umbilical cord stem cells. Teams such as ours, working in good manufacturing practice facilities, will make vectors, essentially “biological delivery vehicles,” carrying a good copy of the broken gene. They will be reinserted into a patient’s cells and then infused back into the patient, much like a bone marrow transplant.

“Perhaps the most promising and exciting research right now comes from combining blood-forming stem cells with gene therapy.”

Along with treating the famous bubble baby disease, where I had started my career, this approach looks very promising for sickle cell anemia. We’re hoping to use it to treat several different inherited metabolic diseases. These are conditions characterized by an abnormal build-up of toxic materials in the body’s cells. They interfere with organ and brain function. It’s caused by just a single enzyme. Using the combined stem cell gene therapy, we can effectively put a good copy of the gene for that enzyme back into a patient’s bone marrow stem cells. Then we do a bone marrow transplantation and bring back a person’s normal functioning cells.

The beauty of this therapy is that it can work for the lifetime of a patient. All of the blood cells circulating in a person’s system would be repaired. It’s the number one stem cell cure happening right now. Plus, it’s a therapy that won’t be rejected. These are a patient’s own stem cells. It is just one type of stem cell, and the first that’s being commercialized to change cells throughout the body.

Q: Let’s step back for a moment. In 2004, voters approved Proposition 71. It has funded a majority of the stem cell research here at UC Davis and throughout California. What’s been the impact of that ballot measure and how is it benefiting patients?

We have learned so much about different types of stem cells, and which stem cell will be most appropriate to treat each type of disease. That’s huge. We had to first do that before being able to start actual stem cell therapies. CIRM [California Institute for Regenerative Medicine] has funded Alpha Stem Cell Clinics. We have one of them here at UC Davis and there are only five in the entire state. These are clinics where the patients can go for high-quality clinical stem cell trials approved by the FDA [U.S. Food and Drug Administration]. They don’t need to go to “unapproved clinics” and spend a lot of money. And they actually shouldn’t.

“By the end of this year, we’ll have 50 clinical trials.”

By the end of this year, we’ll have 50 clinical trials [here at UC Davis Health]. There are that many in the works.

Our Alpha Clinic is right next to the hospital. It’s where we’ll be delivering a lot of the immunotherapies, gene therapies and other treatments. In fact, I might even get to personally deliver stem cells to the operating room for a patient. It will be for a clinical trial involving people who have broken their hip. It’s exciting because it feels full circle, from working in the laboratory to bringing stem cells right to the patient’s bedside.

We have ongoing clinical trials for critical limb ischemia, leukemia and, as I mentioned, sickle cell disease. Our disease teams are conducting stem cell clinical trials targeting sarcoma, cellular carcinoma, and treatments for dysphasia [a swallowing disorder], retinopathy [eye condition], Duchenne muscular dystrophy and HIV. It’s all in the works here at UC Davis Health.

There’s also great potential for therapies to help with renal disease and kidney transplants. The latter is really exciting because it’s like a mini bone marrow transplant. A kidney recipient would also get some blood-forming stem cells from the kidney donor so that they can better accept the organ and not reject it. It’s a type of stem cell therapy that could help address the burden of being on a lifelong regime of immunosuppressant drugs after transplantation.

Q: You and your colleagues get calls from family members and patients all the time. They frequently ask about stem cell “miracle” cures. What should people know about unproven treatments and unregulated stem cell clinics?

That’s a great question.The number one rule is that if you’re asked to pay money for a stem cell treatment, don’t do it. It’s a big red flag.

When it comes to advertised therapies: “The number one rule is that if you’re asked to pay money for a stem cell treatment, don’t do it. It’s a big red flag.”

Unfortunately, there are unscrupulous people out there in “unapproved clinics” who prey on desperate people. What they are delivering are probably not even stem cells. They might inject you with your own fat cells, which contain very few stem cells. Or they might use treatments that are not matched to the patient and will be immediately rejected. That’s dangerous. The FDA is shutting these unregulated clinics down one at a time. But it’s like “whack-a-mole”: shut one down and another one pops right up.

On the other hand, the Alpha Clinic is part of our mission is to help the public get to the right therapy, treatment or clinical trial. The big difference between those who make patients pay huge sums of money for unregulated and unproven treatments and UC Davis is that we’re actually using stem cells. We produce them in rigorously regulated cleanroom facilities. They are certified to contain at least 99% stem cells.

Patients and family members can always call us here. We can refer them to a genuine and approved clinical trial. If you don’t get stem cells at the beginning [of the clinical trial] because you’re part of the placebo group, you can get them later. So it’s not risky. The placebo is just saline. I know people are very, very desperate. But there are no miracle cures…yet. Clinical trials, approved by the FDA, are the only way we’re going to develop effective treatments and cures.

Q: Scientific breakthroughs take a lot of patience and time. How do you and your colleagues measure progress and stay motivated?   

Motivation?  “It’s all for the patients.”

It’s all for the patients. There are not good therapies yet for many disorders. But we’re developing them. Every day brings a triumph. Measuring progress means treating a patient in a clinical trial, or developing something in the laboratory, or getting FDA approval. The big one will be getting biological license approval from the FDA, which means a doctor can prescribe a stem cell or gene therapy treatment. Then it can be covered by a patient’s health insurance.

I’m a cancer survivor myself, and I’m also a heart patient. Our amazing team here at UC Davis has kept me alive and in great health. So I understand it from both sides. I understand the desperation of “Where do I go?” and “What do I do right now?” questions. I also understand the science side of things. Progress can feel very, very slow. But everything we do here at the Institute for Regenerative Cures is done with patients in mind, and safety.

We know that each day is so important when you’re watching a loved one suffer. We attend patient events and are part of things like Facebook groups, where people really pour their hearts out. We say to ourselves, “Okay, we must work harder and faster.” That’s our motivation: It’s all the patients and families that we’re going to help who keep us working hard.

71 for Proposition 71

Proposition 71 is the state ballot initiative that created California’s Stem Cell Agency. This month, the Agency reached another milestone when the 71st clinical trial was initiated in the CIRM Alpha Stem Cell Clinics (ASCC) Network. The ASCC Network deploys specialized teams of doctors, nurses and laboratory technicians to conduct stem cell clinical trials at leading California Medical Centers.

StateClinics_Image_CMYK

These teams work with academic and industry partners to support patient-centered for over 40 distinct diseases including:

  • Amyotrophic Lateral Sclerosis (ALS)
  • Brain Injury & Stroke
  • Cancer at Multiple Sites
  • Diabetes Type 1
  • Eye Disease / Blindness Heart Failure
  • HIV / AIDS
  • Kidney Failure
  • Severe Combined Immunodeficiency (SCID)
  • Sickle Cell Anemia
  • Spinal Cord Injury

These clinical trials have treated over 400 patients and counting. The Alpha Stem Cell Clinics are part of CIRM’s Strategic Infrastructure. The Strategic Infrastructure program which was developed to support the growth of stem cell / regenerative medicine in California. A comprehensive update of CIRM’s Infrastructure Program was provided to our Board, the ICOC.

CIRM’s infrastructure catalyzes stem cell / regenerative medicine by providing resources to all qualified researchers and organizations requiring specialized expertise. For example, the Alpha Clinics Network is supporting clinical trials from around the world.

Many of these trials are sponsored by commercial companies that have no CIRM funding. To date, the ASCC Network has over $27 million in contracts with outside sponsors. These contracts serve to leverage CIRMs investment and provide the Network’s medical centers with a diverse portfolio of clinical trials to address patients’’ unmet medical needs.

Alpha Clinics – Key Performance Metrics

  • 70+ Clinical Trials
  • 400+ Patients Treated
  • 40+ Disease Indications
  • Over $27 million in contracts with commercial sponsors

The CIRM Alpha Stem Cell Clinics and broader Infrastructure Programs are supporting stem cell research and regenerative medicine at every level, from laboratory research to product manufacturing to delivery to patients. This infrastructure has emerged to make California the world leader in regenerative medicine. It all started because California’s residents supported a ballot measure and today we have 71 clinical trials for 71.

 

 

Stories that caught our eye: Is a Texas law opening up access to stem cell treatments working? Another CIRM-funded company gets good news from the FDA.

TexasCapitol_shutterstock_494317324

Texas Capitol. (Shutterstock)

In 2017 Texas passed a sweeping new law, HB 810, which allowed medical clinics to provide “investigational stem cell treatments to patients with certain severe chronic diseases or terminal illnesses.” Those in favor of the law argued that patients battling life-threatening or life-changing diseases should have the right to try stem cell therapies that were involved in a clinical trial.

Now a new study, published in the journal Stem Cells and Development, looks at the impact of the law. The report says that despite some recent amendments t there are still some concerns about the law including:

  • It allows treatment only if the patient has a “severe, chronic” illness but doesn’t define what that means
  • It doesn’t have clearly defined procedures on tracking and reporting procedures so it’s hard to know how many patients might be treated and what the outcomes are
  • There is no Food and Drug Administration (FDA) oversight of the patients being treated
  • Because the treatments are unproven there are fears this will “open up the state to unsavory and predatory practices by individuals preying on vulnerable patients”

The researchers conclude:

“While HB 810 opens up access to patients, it also increases significant risks for their safety and financial cost for something that might have no positive impact on their disease. Truly understanding the impact of stem cell based interventions (SCBI) requires scientific rigor, and accurate outcome data reporting must be pursued to ensure the safety and efficacy behind such procedures. This information must be readily available so that patients can make informed decisions before electing to pursue such treatments. The creation of the SCBI registry could allow for some level of scientific rigor, provide a centralized data source, and offer the potential for better informed patient choices, and might be the best option for the state to help protect patients.”

Another CIRM-funded company gets RMAT designation

Poseida

When Congress approved the 21st Century Cures Act a few years ago one of the new programs it created was the Regenerative Medicine Advanced Therapy (RMAT) designation. This was given to therapies that are designed to treat a serious or life-threatening condition, where early clinical stage trials show the approach is safe and appears to be effective.

Getting an RMAT designation is a big deal. It means the company or researchers are able to apply for an expedited review by the FDA and could get approval for wider use.

This week Poseida Therapeutics was granted RMAT designation by the Food and drug Administration (FDA) for P-BCMA-101, its CAR-T therapy for relapsed/refractory multiple myeloma. This is currently in a Phase 1 clinical trial that CIRM is funding

In this trial Poseida’s technology takes an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy cancerous myeloma cells.

In a news release Eric Ostertag, Poseida’s CEO, welcomed the news:

“Initial Phase 1 data presented at the CAR-TCR Summit earlier this year included encouraging response rates and safety data, including meaningful responses in a heavily pretreated population. We expect to have an additional data update by the end of the year and look forward to working closely with the FDA to expedite development of P-BCMA-101.”

This means that five CIRM-funded companies have now been granted RMAT designations:

Deep dive into muscle repair yields new strategies to combat Duchenne muscular dystrophy

Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) reported new findings this week that may lead to novel therapeutic strategies for people suffering from Duchenne muscular dystrophy (DMD). DMD, a muscle-wasting disease that affects 1 in 7250 males aged 5 to 24 years in the United States, is caused by a genetic mutation leading to the lack of a protein called dystrophin. Without dystrophin, muscle cells become fragile and are easily damaged. Instead of self-repair, the muscles are replaced by scar tissue, a process called fibrosis that leads to muscle degeneration and wasting.

DMD_KhanAcademy

Dystrophin, a protein that maintains the structural integrity of muscle fibers, is missing in people with DMD. Image credit: Khan Academy

Boys with DMD first show signs of muscle weakness between ages 3-5 and often stop walking by the time they’re teenagers. Eventually the muscles critical for breathing and heart function stop working. Average life expectancy is 26 and there is no cure.

The SBP scientists are aiming to treat DMD by boosting muscle repair in affected individuals. But to do that, they sought to better understand how muscle regeneration works in the first place. In the current study, they focused their efforts on so-called fibro/adipogenic precursor (FAP) cells which, in response to acute injury, appear to play a role in stimulating muscle stem cells to divide and replace damaged muscle in healthy individuals. But FAPs are also implicated in the muscle wasting and scarring that’s seen in DMD.

By examining the gene activity of single FAP cells from mouse models of acute injury and DMD, the researchers identified a sub-population of FAP cells (sub-FAPs). Further study of these sub-FAPs showed that during early stages of muscle regeneration, these cells promote muscle stem cell activation but then at later stages, sub-FAPs – identified by a cell surface protein called Vcam1 – stimulate fibrosis. It turns out that during healthy acute muscle injury, the sub-FAPs with cell-surface Vcam1 protein are readily eaten up and removed by immune cells thereby avoiding muscle fibrosis. But in the DMD mouse model, removal of these sub-FAPs is impaired and instead collagen deposits and muscle fibrosis occur which are hallmarks of the progressive degeneration seen in DMD.

Barbora Malecova, Ph.D., a first author of the study, explained the implications of these results in a press release:

“This study elucidates the cellular and molecular pathogenesis of muscular dystrophy. These results indicate that removing or modulating the activity of Vcam1-positive sub-FAPs, which promote fibrosis, could be an effective treatment for DMD.”

The lab, led by Pier Lorenzo Puri, M.D., next will explore the possibility of finding drugs that target the Vcam1 sub-FAPs which in turn could help prevent fibrosis in DMD.

The study, funded in part by CIRM, appears in Nature Communications. CIRM is also funding a Phase 2 clinical trial testing a stem cell-based therapy that aims to improve the life-threatening heart muscle degeneration that occurs in DMD patients.

New CIRM Alpha Stem Cell Clinic offers HOPE for boys with deadly disease

UC Davis Institute for Regenerative Cures

For people battling Duchenne Muscular Dystrophy (DMD), a rare and fatal genetic disorder that slowly destroys muscles, hope has often been in short supply. There is no cure and treatments are limited. But now a new clinical trial at the site of one of the newest CIRM Alpha Stem Cell Clinic Network members could change that.

The HOPE-2 clinical trial has treated its first patient at UC Davis Medical Center, inaugurating the institution’s Alpha Stem Cell Clinic. The clinic is part of a CIRM-created network of top California medical centers that specialize in delivering stem cell clinical trials to patients. The key to the Network’s success is the ability to accelerate the delivery of treatments to patients through partnerships with patients, medical providers and clinical trial sponsors.

UC Davis is one of five medical centers that now make up the network (the others are UC San Francisco, UCLA/UC Irvine, UC San Diego and City of Hope).

Jan NoltaIn a news release, Jan Nolta, the director of the UC Davis Institute for Regenerative Cures, says the UC Davis Alpha Clinic is well equipped to move promising therapies out of the lab and into clinical trials and people.

“We have the full range of resource experts in regenerative medicine, from the cellular to the clinical trials level. We’re also excited about the prospect of being able to link with other Alpha Stem Cell Clinics around the state to help speed the process of testing and refining treatments so we can get therapies to patients in need.”

The news of this first patient is a cause for double celebration at CIRM. The trial is run by Capricor and CIRM funded the first phase of this work. You can read the story of Caleb Sizemore, who took part in that trial or watch this video of him talking about his fight.

When the CIRM Board approved funding for the UC Davis Alpha Clinic in October of 2017, Abla Creasey, CIRM’s Vice President for Therapeutics and Strategic Infrastructure, said:

“The Alpha Clinics are a one-of-a-kind network that gives patients access to the highest quality stem cell trials for a breadth of diseases including cancer, diabetes, heart disease and spinal cord injury. Expanding our network will allow more patients to participate in stem cell trials and will advance the development of stem cell treatments that could help or possibly cure patients.”

The UC Davis Alpha Clinic provides a one-stop shop for delivering stem cell therapies, gene therapies and immunotherapies, as well as conducting follow-up visits. It’s this type of CIRM-funded infrastructure that helps steer potential clinical trial participants away from illegitimate, unproven and potentially harmful fee-for-service stem cell treatments.

The DMD trial is the first of what we are confident will be many high-quality trials at the Clinic, bringing promising stem cell therapies to patients with unmet medical needs.

 

UCLA scientists on track to develop a stem cell replacement therapy for Duchenne Muscular Dystrophy

Muscle cells generated by April Pyle’s Lab at UCLA.

Last year, we wrote about a CIRM-funded team at UCLA that’s on a mission to develop a stem cell treatment for patients with Duchenne muscular dystrophy (DMD). Today, we bring you an exciting update on this research just in time for the holidays (Merry Christmas and Happy Hanukkah and Kwanza to our readers!).

DMD is a deadly muscle wasting disease that primarily affects young boys and young men. The UCLA team is trying to generate better methods for making skeletal muscle cells from pluripotent stem cells to regenerate the muscle tissue that is lost in patients with the condition. DMD is caused by genetic mutations in the dystrophin gene, which codes for a protein that is essential for skeletal muscle function. Without dystrophin protein, skeletal muscles become weak and waste away.

In their previous study, the UCLA team used CRISPR gene editing technology to remove dystrophin mutations in induced pluripotent stem cells (iPSCs) made from the skin cells of DMD patients. These corrected iPSCs were then matured into skeletal muscle cells that were transplanted into mice. The transplanted muscle cells successfully produced dystrophin protein – proving for the first time that DMD mutations can be corrected using human iPSCs.

A Step Forward

The team has advanced their research a step forward and published a method for making skeletal muscle cells, from DMD patient iPSCs, that look and function like real skeletal muscle tissue. Their findings, which were published today in the journal Nature Cell Biology, address a longstanding problem in the field: not being able to make stem cell-derived muscle cells that are mature enough to model DMD or to be used for cell replacement therapies.

Dr. April Pyle, senior author on the study and Associate Professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA explained in a news release:

April Pyle, UCLA.

“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional. For a stem cell therapy for Duchenne to move forward, we must have a better understanding of the cells we are generating from human pluripotent stem cells compared to the muscle stem cells found naturally in the human body and during the development process.”

By comparing the proteins expressed on the cell surface of human fetal and adult muscle cells, the team identified two proteins, ERBB3 and NGFR, that represented a regenerative population of skeletal muscle cells. They used these two markers to isolate these regenerative muscle cells, but found that the muscle fibers they created in a lab dish were smaller than those found in human muscle.

First author, Michael Hicks, discovered that using a drug to block a human developmental signaling pathway called TGF Beta pushed these ERBB3/NGFR cells past this intermediate stage and allowed them to mature into functional skeletal muscle cells similar to those found in human muscle.

Putting It All Together

In their final experiments, the team combined the new stem cell techniques developed in the current study with their previous work using CRISPR gene editing technology. First, they removed the dystrophin mutations in DMD patient iPSCs using CRISPR. Then, they coaxed the iPSCs into skeletal muscle cells in a dish and isolated the regenerative cells that expressed ERBB3 and NGFR. Mice that lacked the dystrophin protein were then transplanted with these cells and were simultaneously given an injection of a TGF Beta blocking drug.

The results were exciting. The transplanted cells were able to produce human dystrophin and restore the expression of this protein in the Duchenne mice.

Skeletal muscle cells isolated using the ERBB3 and NGFR surface markers (right) restore human dystrophin (green) after transplantation significantly greater than previous methods (left). (Image courtesy of UCLA)

Dr. Pyle concluded,

“The results were exactly what we’d hoped. This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”

In the long term, the UCLA team hopes to translate this research into a patient-specific stem cell therapy for DMD patients. In the meantime, the team will use funding from a recent CIRM Quest award to make skeletal muscle cells that can regenerate long-term in response to chronic injury in hopes of developing a more permanent treatment for DMD.

The UCLA study discussed in this blog received funding from Discovery stage CIRM awards, which you can read more about here and here.

Stem Cell Stories That Caught our Eye: Stem Cell Therapies for Stroke and Duchenne Muscular Dystrophy Patients

With the Thanksgiving holiday behind us, we’re back to the grind at CIRM. Here are two exciting CIRM-funded stem cell stories that happened while you were away.

Stanford Scientists Are Treating Stroke Patients with Stem Cells

Smithsonian Magazine featured the work of a CIRM-funded scientist in their December Magazine issue. The article, “A Neurosurgeon’s Remarkable Plan to Treat Stroke Victims with Stem Cells”, features Dr. Gary Steinberg, who is the Chair of Neurosurgery at Stanford Medical Center and the founder of the Stanford Stroke Center.

Gary Steinberg (Photo by Jonathan Sprague)

The brain and its 100 billion cells need blood, which carries oxygen and nutrients, to function. When that blood supply is cut off, brain cells start to die and patients experience a stroke. Stroke can happen in one of two ways: either by blood clots that block the arteries and blood vessels that send blood to the brain or by blood vessels that burst within the brain itself. Symptoms experienced by stroke victims vary based on the severity of the stroke, but often patients report experiencing numbness or paralysis in their limbs or face, difficulty walking, talking and understanding.

Steinberg and his team at Stanford are developing a stem cell treatment to help stroke patients. Steinberg believes that not all brain cells die during a stroke, but rather some brain cells become “dormant” and stop functioning instead. By transplanting stem cells derived from donated bone marrow into the brains of stroke patients, Steinberg thinks he can wake up these dormant cells much like how the prince wakens Sleeping Beauty from her century of enchanted sleep.

Basically, the transplanted cells act like a defibrillator for the dormant cells in the stroke-damaged area of the brain. Steinberg thinks that the transplanted cells secrete proteins that signal dormant brain cells to wake up and start functioning normally again, and that they also trigger a “helpful immune response” that prompts the brain to repair itself.

Sonia has seen first hand how a stroke can rob you of even your most basic abilities.

Steinberg tested this stem cell treatment in a small clinical trial back in 2013. 18 patients were treated and many of them showed improvements in their symptoms. The Smithsonian piece mentions a particular patient who had a remarkable response to the treatment. Sonia Olea Coontz, at age 32, suffered a stroke that robbed her of most of her speech and her ability to use her right arm and leg. After receiving Steinberg’s stem cell treatment, Sonia rapidly improved and was able to raise her arm above her head and gained most of her speech back. You can read more about her experience in our Stories of Hope.

In collaboration with a company called SanBio, Steinberg’s team is now testing this stem cell therapy in 156 stroke patients in a CIRM-funded phase 2 clinical trial. The trial will help answer the question of whether this treatment is safe and also effective in a larger group of patients.

The Smithsonian article, which I highly recommend reading, shared Steinberg’s future aspirations to pursue stem cell therapies for traumatic brain and spinal cord injuries as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS.

 

Capricor Approved to Launch New Clinical Trial for Duchenne Muscular Dystrophy

On Wednesday, Capricor Therapeutics achieved an exciting milestone for its leading candidate CAP-1002 – a stem cell-based therapy developed to treat boys and young men with a muscle-wasting disease called Duchenne muscular dystrophy (DMD).

The Los Angeles-based company announced that it received approval from the US Food and Drug Administration (FDA) for their investigational new drug (IND) application to launch a new clinical trial called HOPE II that’s testing repeated doses of CAP-1002 cells in DMD patients. The cells are derived from donated heart tissue and are believed to release regenerative factors that strengthen heart and other muscle function in DMD patients.

Capricor is currently conducting a Phase 2 trial, called HOPE-1, that’s testing a single dose of CAP-1002 cells in 24 DMD patients. CIRM is funding this trial and you can learn more about it on our clinical dashboard website and watch a video interview we did with a young man who participated in the trial.

Earlier this year, the company shared encouraging, positive results from the HOPE-1 trial suggesting that the therapy was improving some heart function and upper limb movement six months after treatment and was well-tolerated in patients. The goal of the new trial will be to determine whether giving patients repeated doses of the cell therapy over time will extend the benefits in upper limb movement in DMD patients.

In a news release, Capricor President and CEO Dr. Linda Marbán shared her company’s excitement for the launch of their new trial and what this treatment could mean for DMD patients,

Linda Marban, CEO of Capricor Therapeutics

“The FDA’s clearance of this IND upon its initial submission is a significant step forward in our development of CAP-1002. While there are many clinical initiatives in Duchenne muscular dystrophy, this is one of the very few to focus on non-ambulant patients. These boys and young men are looking to maintain what function they have in their arms and hands and, based on our previous study, we think CAP-1002 may be able to do exactly that.”