Inspiring new documentary about stem cell research

Poster for the documentary “Ending Disease”

2020 has been, to say the very least, a difficult and challenging year for all of us. But while the focus of the world has, understandably, been on the coronavirus there was also some really promising advances in stem cell research. Those advances are captured in a great new documentary called Ending Disease.

The documentary is by Emmy award-winning filmmaker Joe Gantz. In it he follows ten people who are facing life-threatening or life-changing diseases and injuries and who turn to pioneering stem cell therapies for help.

It’s an inspiring documentary, one that reminds you of the real need for new treatments and the tremendous hope and promise of stem cell therapies. Here’s a look at a trailer for Ending Disease.

You can see an exclusive screening of Ending Disease on Friday, January 8th, 2021 at 5:00pm PST.

After the livestream, there will be a live Q&A session where former members of the successful Proposition 14 campaign team – which refunded CIRM with an additional $5.5 billion – will be joined by CIRM’s President and CEO Dr. Maria Millan, talking about what lies ahead for CIRM and the future of stem cell research.

To purchase a ticket, click here. It only costs $12 and 50% of the ticket sales proceeds will go to Americans for Cures to help them continue to advocate for the advancement of stem cell research, and more importantly, for the patients and families to whom stem cell research provides so much hope.

If you need any extra persuading that it’s something you should definitely put on our calendar, here’s a letter from the film maker Joe Gantz.

I am the director of the documentary Ending Disease: The Stem Cell, Anti-Cancer T-Cell, & Antibody Revolution In Medicine, a film that will help inform people about the progress that’s been made in this field and how people with their lives on the line are now able to benefit from these new regenerative therapies. 

I was granted unprecedented access to ten of the first generation of clinical trials using stem cell and regenerative medicine to treat and cure many of the most devastating diseases and conditions including: brain cancer, breast cancer, leukemia and lymphoma, HIV, repairing a broken spinal cord, retinitis pigmentosa and SCID. The results are truly inspiring.

This is personal for me.  After spending four years making this documentary, I was diagnosed with bladder cancer. Upon diagnosis, I immediately felt the same desperation as millions of families who are in search of a medical breakthrough. I understood, on a personal level, what the patients we followed in the film all knew: when you are diagnosed with a disease, there is a narrow window of time in which you can effectively seek a life-saving treatment or cure. If treatment becomes available outside of that window, then it is too late. However, Ending Disease shows that with continued support for regenerative medicine, we can create a near future in which one-time cures and highly mitigating therapies are available to patients for a whole host of diseases.

Best regards,

Joe

Repairing damaged muscles

Close-up of the arm of a 70-year-old male patient with a torn biceps muscle as a result of a bowling injury; Photo courtesy Science Photo Library

In the time of coronavirus an awful lot of people are not just working from home they’re also working out at home. That’s a good thing; exercise is a great way to boost the immune system, stay healthy and deal with stress. But for people used to more structured workouts at the gym it can come with a downside. Trying new routines at home that look easy on YouTube, but are harder in practice could potentially increase the risk of injury.

A new study from Japan looks at what happens when you damage a muscle. It won’t help it heal faster, but it will at least let you understand what is happening inside your body as you sit there with ice on your arm and ibuprofen in your hand.

The researchers found that when you damage a muscle, for example by trying to lift too much weight or doing too many repetitions of one exercise, the damaged muscle fibers leak substances that activate nearby “satellite” stem cells. These satellite cells then flock to the site of the injury and help repair the muscle.

The team, from Kumamoto University and Nagasaki University in Japan, named the leaking substances “Damaged myofiber-derived factors” (DMDFs) – personally I think “Substances Leaked by Injured Muscles (SLIM) would be a much cooler acronym, but that’s just me. Gaining a deeper understanding of how DMDFs work might help lead to therapies for older people who have fewer satellite muscle cells, and also for conditions like muscular dystrophy and age-related muscular fragility (sarcopenia), where the number and function of satellite cells decreases.

In an article in Science Daily, Professor Yusuke Ono, the leader of the study, says it’s possible that DMDFs play an even greater role in the body:

“In this study, we proposed a new muscle injury-regeneration model. However, the detailed molecular mechanism of how DMDFs activate satellite cells remains an unclear issue for future research. In addition to satellite cell activation, DMDF moonlighting functions are expected to be diverse. Recent studies have shown that skeletal muscle secretes various factors that affect other organs and tissues, such as the brain and fat, into the bloodstream, so it may be possible that DMDFs are involved in the linkage between injured muscle and other organs via blood circulation. We believe that further elucidation of the functions of DMDFs could clarify the pathologies of some muscle diseases and help in the development of new drugs.”

The study appears in the journal Stem Cell Reports.

Perseverance: from theory to therapy. Our story over the last year – and a half

Some of the stars of our Annual Report

It’s been a long time coming. Eighteen months to be precise. Which is a peculiarly long time for an Annual Report. The world is certainly a very different place today than when we started, and yet our core mission hasn’t changed at all, except to spring into action to make our own contribution to fighting the coronavirus.

This latest CIRM Annual Reportcovers 2019 through June 30, 2020. Why? Well, as you probably know we are running out of money and could be funding our last new awards by the end of this year. So, we wanted to produce as complete a picture of our achievements as we could – keeping in mind that we might not be around to produce a report next year.

Dr. Catriona Jamieson, UC San Diego physician and researcher

It’s a pretty jam-packed report. It covers everything from the 14 new clinical trials we have funded this year, including three specifically focused on COVID-19. It looks at the extraordinary researchers that we fund and the progress they have made, and the billions of additional dollars our funding has helped leverage for California. But at the heart of it, and at the heart of everything we do, are the patients. They’re the reason we are here. They are the reason we do what we do.

Byron Jenkins, former Naval fighter pilot who battled back from his own fight with multiple myeloma

There are stories of people like Byron Jenkins who almost died from multiple myeloma but is now back leading a full, active life with his family thanks to a CIRM-funded therapy with Poseida. There is Jordan Janz, a young man who once depended on taking 56 pills a day to keep his rare disease, cystinosis, under control but is now hoping a stem cell therapy developed by Dr. Stephanie Cherqui and her team at UC San Diego will make that something of the past.

Jordan Janz and Dr. Stephanie Cherqui

These individuals are remarkable on so many levels, not the least because they were willing to be among the first people ever to try these therapies. They are pioneers in every sense of the word.

Sneha Santosh, former CIRM Bridges student and now a researcher with Novo Nordisk

There is a lot of information in the report, charting the work we have done over the last 18 months. But it’s also a celebration of everyone who made it possible, and our way of saying thank you to the people of California who gave us this incredible honor and opportunity to do this work.

We hope you enjoy it.

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.

Promising results from CIRM-funded projects

Severe Leukocyte Adhesion Deficiency-1 (LAD-1) is a rare condition that causes the immune system to malfunction and reduces its ability to fight off viruses and bacteria. Over time the repeated infections can take a heavy toll on the body and dramatically shorten a person’s life. But now a therapy, developed by Rocket Pharmaceuticals, is showing promise in helping people with this disorder.

The therapy, called RP-L201, targets white blood cells called neutrophils which ordinarily attack and destroy invading particles. In people with LAD-1 their neutrophils are dangerously low. That’s why the new data about this treatment is so encouraging.

In a news release, Jonathan Schwartz, M.D., Chief Medical Officer of Rocket, says early results in the CIRM-funded clinical trial, show great promise:

“Patients with severe LAD-I have neutrophil CD18 expression of less than 2% of normal, with extremely high mortality in early childhood. In this first patient, an increase to 47% CD18 expression sustained over six months demonstrates that RP-L201 has the potential to correct the neutrophil deficiency that is the hallmark of LAD-I. We are also pleased with the continued visible improvement of multiple disease-related skin lesions. The second patient has recently been treated, and we look forward to completing the Phase 1 portion of the registrational trial for this program.”

The results were released at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy.

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These microscopic images show gene expression in muscle stem and progenitor cells as they mature from early development to adulthood (left to right). As part of this process, the cells switch from actively expressing one key gene (green) to another (violet); this is accompanied by the growth of muscle fibers (red).
Photo courtesy: Cell Stem Cell/UCLA Broad Stem Cell Research Center

When you are going on a road-trip you need a map to help you find your way. It’s the same with stem cell research. If you are going to develop a new way to treat devastating muscle diseases, you need to have a map to show you how to build new muscle stem cells. And that’s what researchers at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA – with help from CIRM funding – have done.

The team took muscle progenitor cells – which show what’s happening in development before a baby is born – and compared them to muscle stem cells – which control muscle development after a baby is born. That enabled them to identify which genes are active at what stage of development.

In a news release, April Pyle, senior author of the paper, says this could open the door to new therapies for a variety of conditions:

“Muscle loss due to aging or disease is often the result of dysfunctional muscle stem cells. This map identifies the precise gene networks present in muscle progenitor and stem cells across development, which is essential to developing methods to generate these cells in a dish to treat muscle disorders.”

The study is published in the journal Cell Stem Cell.

Tiny organs grown from snake stem cells produce real venom

Researchers grew tiny venom glands from nine different snake species, including the cape coral cobra pictured above.
Photo Credit: Michael D. Kern/Science Source

Snake venom can be deadly without proper treatment. Interestingly enough, it may also hold the key for treatments against pain, high blood pressure, and cancer according to one analysis. Despite this, scientists still do not understand much about the biology behind the wide range of different snake venoms, which can make it challenging to develop effective treatments in the event of snake bites.

Fortunately, a new study by Dr. Hans Clevers and his team at the Hubrecht Institute in the Netherlands could significantly aid the understanding of snake venom. Dr. Clevers and his team were able to grow miniature snake venom glands using snake stem cells. What’s more remarkable is that these “mini-organs” produced real venom!

Miniature, lab-grown snake venom glands
 Photo Credit: Ravian van Ineveld/Princess Maxima Center

In an article posted in Science Magazine, Dr. Clevers talks about how his study was navigating uncharted waters.

“Nobody knew anything about stem cells in snakes. We didn’t know if it was possible at all.”

To produce these “mini-organs”, the researchers removed the stem cells from the venom glands of nine different types of snake and placed them in a mixture of growth factors that contained different hormones and proteins. It turns out that the snake stem cells responded to the same factors used on human and mouse stem cells.

Eventually, the stem cells grew into little clumps of tissue and when the researchers removed the growth factors, they started to change into the same kind of cells that produce venom in the glands of snakes. Additionally, they were able to find that these “mini-organs” expressed similar genes as those observed in real venom glands.

The scientists were even able to test the nature of the “mini-organ” venom as well. A chemical and genetic analysis of the venom revealed that it matched the one made by real snakes. After testing this venom on mouse muscle cells and rat neurons, they also found that it damaged these cells similar to real venom.

The type of toxins and concentration levels can vary drastically in snake venom, even within the same species. This can make developing treatments challenging since they can only be used to combat one type of venom.

Dr. Clevers and his team now plan to study the complexities of venom and venom glands by compiling a “biobank” of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. With the aid of their newly developed “mini-organs”, all of this can be done without the handling of live, dangerous snakes, some of which are rare and difficult to keep in captivity.

The full results of this study were published in Cell.

New findings about muscle stem cells reveals the potential for growing replacement organs

Chrissa Kioussi’s group at Oregon State University has made exciting advances in further unraveling the scientific mysteries of stem cells. In work detailed in Scientific Reports, this group found that muscle-specific stem cells actually have the ability to make multiple different cell types.

muscle_bicep_FaceBook_shutterstock_162592241

Pumping up our knowledge about muscle stem cells

Initially, this group was interested in understanding how gene expression changes during embryonic development of skeletal muscle. To understand this process, they labeled muscle stem cells with a kind of fluorescent dye, called GFP, which allowed them to isolate these cells at different stages of development.  Once isolated, they determined what genes were being expressed by RNA sequencing. Surprisingly, they found that in addition to genes involved in muscle formation, they also identified activation of genes involved in the blood, nervous, immune and skeletal systems.

This work is particularly exciting, because it suggests the existence of stem cell “pockets,” or stem cells that are capable of not only making a specific cell type, but an entire organ system.

In a press release, Dr. Kioussi said:

chrissa_kioussi

Chrissa Kioussi, PhD

“That cell populations can give rise to so many different cell types, we can use it at the development stage and allow it to become something else over time… We can identify these cells and be able to generate not one but four different organs from them — this is a prelude to making body parts in a lab.” 

This study is particularly exciting because it gives more credence to the idea that entire limbs can be reconstructed from a small group of stem cells. Such advances could have enormous meaning for individuals who have lost body parts due to amputation or disease.

Giving thanks to Caleb and all of our stem cell pioneers [Video]

For our last blog before the Thanksgiving holiday, we give thanks to the patients and their caregivers who are forging a path toward a new era of regenerative medicine therapies through their participation in CIRM-funded clinical trials.

Some of our trials are in the early stages which means they are mainly focused on safety. Participants go into these trials knowing that the cell therapy dose they receive will probably be too low to get any benefit for themselves. And in later trials, some patients will receive a placebo, or blank therapy, for comparison purposes. Even if a patient gets an effective dose, it may not work for them. So the decision to enroll in an experimental clinical trial is often a selfless act. Yet final approval of a therapy by the U.S. Food and Drug Administration (and other regulatory agencies around the world) depends on these brave souls and for that we are truly grateful.

So, with this Thanksgiving Day spirit in mind, we leave you with our latest video featuring Caleb Sizemore, a charming young man who epitomizes the courage of our clinical trial pioneers. At just 7 years old, Caleb was diagnosed with Duchenne Muscular Dystrophy (DMD), a degenerative muscle disease which makes it difficult for him to walk and climb stairs, has led to dangerous scarring of his heart muscle and carries a shortened life expectancy with most DMD patients not living past their 20s or 30s.

In a sit-down interview with us and in clips from his June 2017 presentation to the CIRM governing Board, Caleb talked about the impact of DMD on his life and his experience enrolling in Capricor Therapeutics’ CIRM-funded clinical trial. The trial is testing a stem cell therapy designed to repair the heart scarring that occurs with DMD. By the end of the three-minute video, I can assure you that you’ll be as captivated as we were by Caleb’s delightful, sincere and full-of-faith personality.

The life of a sleeping muscle stem cell is very busy

For biological processes, knowing when to slow down is as important as knowing when to step on the accelerator. Take for example muscle stem cells. In a healthy state, these cells mostly lay quiet and rarely divide but upon injury, they bolt into action by dividing and specializing into new muscle cells to help repair damaged muscle tissue. Once that mission is accomplished, the small pool of muscle stem cells is replenished through self-renewal before going back into a dormant, or quiescent, state.

muscle stem cell

Muscle stem cell (pink with green outline) sits along a muscle fiber. Image: Michael Rudnicki/OIRM

“Dormant” may not be the best way to describe it because a lot of activity is going on within the cells to maintain its sleepy state. And a better understanding of the processes at play in a dormant state could reveal insights about treating aging or diseased muscles which often suffer from a depletion of muscle stem cells. One way to analyze cellular activity is by examining RNA transcripts which are created when a gene is turned “on”. These transcripts are the messenger molecules that provide a gene’s instructions for making a particular protein.

By observing something, you change it
In order to carry out the RNA transcript analyses in animal studies, researchers must isolate and purify the stem cells from muscle tissue. The worry here is that all of the necessary poking of prodding of the cells during the isolation method will alter the RNA transcripts leading to a misinterpretation of what is actually happening in the native muscle tissue. To overcome this challenge, Dr. Thomas Rando and his team at Stanford University applied a recently developed technique that allowed them to tag and track the RNA transcripts within living mice.

The CIRM-funded study reported today in Cell Reports found that there are indeed significant differences in results when comparing the standard in vitro lab method to the newer in vivo method. As science writer Krista Conger summarized in a Stanford Medical School press release, those differences led to some unexpected results that hadn’t been observed previously:

“The researchers were particularly surprised to learn that many of the RNAs made by the muscle stem cells in vivo are either degraded before they are made into proteins, or they are made into proteins that are then rapidly destroyed — a seemingly shocking waste of energy for cells that spend most of their lives just cooling their heels along the muscle fiber.”

It takes a lot of energy to stay ready
Dr. Rando thinks that these curious observations do not point to an inefficient use of a cell’s resources but instead, “it’s possible that this is one way the cells stay ready to undergo a rapid transformation, either by blocking degradation of RNA or proteins or by swiftly initiating translation of already existing RNA transcripts.”

The new method provides Rando’s team a whole new perceptive on understanding what’s happening behind the scenes during a muscle stem cell’s “dormant” state. And Rando thinks the technique has applications well beyond this study:

Rando

Thomas Rando

“It’s so important to know what we are and are not modeling about the state of these cells in vivo. This study will have a big impact on how researchers in the field think about understanding the characteristics of stem cells as they exist in their native state in the tissue.”

 

 

Stem cell agency funds Phase 3 clinical trial for Lou Gehrig’s disease

ALS

At CIRM we don’t have a disease hierarchy list that we use to guide where our funding goes. We don’t rank a disease by how many people suffer from it, if it affects children or adults, or how painful it is. But if we did have that kind of hierarchy you can be sure that Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, would be high on that list.

ALS is a truly nasty disease. It attacks the neurons, the cells in our brain and spinal cord that tell our muscles what to do. As those cells are destroyed we lose our ability to walk, to swallow, to talk, and ultimately to breathe.

As Dr. Maria Millan, CIRM’s interim President and CEO, said in a news release, it’s a fast-moving disease:

“ALS is a devastating disease with an average life expectancy of less than five years, and individuals afflicted with this condition suffer an extreme loss in quality of life. CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and, in keeping with this mission, our objective is to find a treatment for patients ravaged by this neurological condition for which there is currently no cure.”

Having given several talks to ALS support groups around the state, I have had the privilege of meeting many people with ALS and their families. I have seen how quickly the disease works and the devastation it brings. I’m always left in awe by the courage and dignity with which people bear it.

BrainStorm

I thought of those people, those families, today, when our governing Board voted to invest $15.9 million in a Phase 3 clinical trial for ALS run by BrainStorm Cell Therapeutics. BrainStorm is using mesenchymal stem cells (MSCs) that are taken from the patient’s own bone marrow. This reduces the risk of the patient’s immune system fighting the therapy.

After being removed, the MSCs are then modified in the laboratory to  boost their production of neurotrophic factors, proteins which are known to help support and protect the cells destroyed by ALS. The therapy, called NurOwn, is then re-infused back into the patient.

In an earlier Phase 2 clinical trial, NurOwn showed that it was safe and well tolerated by patients. It also showed evidence that it can help stop, or even reverse  the progression of the disease over a six month period, compared to a placebo.

CIRM is already funding one clinical trial program focused on treating ALS – that’s the work of Dr. Clive Svendsen and his team at Cedars Sinai, you can read about that here. Being able to add a second project, one that is in a Phase 3 clinical trial – the last stage before, hopefully, getting approval from the Food and Drug Administration (FDA) for wider use – means we are one step closer to being able to offer people with ALS a treatment that can help them.

Diane Winokur, the CIRM Board Patient Advocate member for ALS, says this is something that has been a long time coming:

CIRM Board member and ALS Patient Advocate Diane Winokur

“I lost two sons to ALS.  When my youngest son was diagnosed, he was confident that I would find something to save him.  There was very little research being done for ALS and most of that was very limited in scope.  There was one drug that had been developed.  It was being released for compassionate use and was scheduled to be reviewed by the FDA in the near future.  I was able to get the drug for Douglas.  It didn’t really help him and it was ultimately not approved by the FDA.

When my older son was diagnosed five years later, he too was convinced I would find a therapy.  Again, I talked to everyone in the field, searched every related study, but could find nothing promising.

I am tenacious by nature, and after Hugh’s death, though tempted to give up, I renewed my search.  There were more people, labs, companies looking at neurodegenerative diseases.

These two trials that CIRM is now funding represent breakthrough moments for me and for everyone touched by ALS.  I feel that they are a promising beginning.  I wish it had happened sooner.  In a way, though, they have validated Douglas and Hugh’s faith in me.”

These therapies are not a cure for ALS. At least not yet. But what they will do is hopefully help buy people time, and give them a sense of hope. For a disease that leaves people desperately short of both time and hope, that would be a precious gift. And for people like Diane Winokur, who have fought so hard to find something to help their loved ones, it’s a vindication that those efforts have not been in vain.