Exploring tough questions, looking for answers

COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.

The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.

But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.

One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.

Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.

Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.

How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.

It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.

Here’s where you can register and find out more about the Symposium

Building a progressive pipeline

Dr. Kelly Shepard

By Dr. Kelly Shepard

One of our favorite things to do at CIRM is deliver exciting news about CIRM projects. This usually entails discussion of recent discoveries that made headlines, or announcing the launch of a new CIRM-funded clinical trial …. tangible signs of progress towards addressing unmet medical needs through advances in stem technology.

But there are equally exciting signs of progress that are not always so obvious to the untrained eye-  those that we are privileged to witness behind the scenes at CIRM. These efforts don’t always lead to a splashy news article or even to a scientific publication, but they nonetheless drive the evolution of new ideas and can help steer the field away from futile lines of investigation. Dozens of such projects are navigating uncharted waters by filling knowledge gaps, breaking down technical barriers, and working closely with regulatory agencies to define novel and safe paths to the clinic.

These efforts can remain “hidden” because they are in the intermediate stages of the long, arduous and expensive journey from “bench to beside”.  For the pioneering projects that CIRM funds, this journey is unique and untrod, and can be fraught with false starts. But CIRM has developed tools to track the momentum of these programs and provide continuous support for those with the most promise. In so doing, we have watched projects evolve as they wend their way to the clinic. We wanted to share a few examples of how we do this with our readers, but first… a little background for our friends who are unfamiliar with the nuts and bolts of inventing new medicines.

A common metaphor for bringing scientific discoveries to market is a pipeline, which begins in a laboratory where a discovery occurs, and ends with government approval to commercialize a new medicine, after it is proven to be safe and effective. In between discovery and approval is a stage called “Translation”, where investigators develop ways to transition their “research level” processes to “clinically compatible” ones, which only utilize substances that are of certified quality for human use. 

Investigators must also work out novel ways to manufacture the product at larger scale and transition the methods used for testing in animal models to those that can be implemented in human subjects.

A key milestone in Translation is the “preIND” (pre Investigational New Drug (IND) meeting, where an investigator presents data and plans to the US Food and Drug Administration (FDA) for feedback before next stage of development begins, the pivotal testing needed to show it is both safe and effective.

These “IND enabling studies” are rigorous but necessary to support an application for an IND and the initiation of clinical trials, beginning with phase 1 to assess safety in a small number of individuals, and phase 2, where an expanded group is evaluated to see if the therapy has any benefits for the patient. Phase 3 trials are studies of very large numbers of individuals to gain definitive evidence of safety and therapeutic effect, generally the last step before applying to the FDA for market approval. An image of the pipeline and the stages described are provided in our diagram below.

The pipeline can be notoriously long and tricky, with plenty of twists, turns, and unexpected obstacles along the way. Many more projects enter than emerge from this gauntlet, but as we see from these examples of ‘works in progress”, there is a lot of momentum building.

Caption for Graphic: This graphic shows the number of CIRM-funded projects and the stages they have progressed through multiple rounds of CIRM funding. For example, the topmost arrow shows that are about 19 projects at the translational stage of the pipeline that received earlier support through one of CIRM’s Discovery stage programs. Many of these efforts came out of our pre-2016 funding initiatives such as Early Translation, Basic Biology and New Faculty Awards. In another example, you can see that about 15 awards that were first funded by CIRM at the IND enabling stage have since progressed into a phase 1 or phase 2 clinical trials. While most of these efforts also originated in some of CIRM’s pre-2016 initiatives such as the Disease Team Awards, others have already progressed from CIRM’s newer programs that were launched as part of the “2.0” overhaul in 2016 (CLIN1).

The number of CIRM projects that have evolved and made their way down the pipeline with CIRM support is impressive, but it is clearly an under-representation, as there are other projects that have progressed outside of CIRM’s purview, which can make things trickier to verify.

We also track projects that have spun off or been licensed to commercial organizations, another very exciting form of “progression”. Perhaps those will contribute to another blog for another day! In the meantime, here are a just a few examples of some of the progressors that are depicted on the graphic.

Project: stem cell therapy to enhance bone healing in the elderly

– Currently funded stage: IND enabling development, CLIN1-11256 (Dr. Zhu, Ankasa Regenerative Therapeutics)

– Preceded by preIND-enabling studies, TRAN1-09270 (Dr. Zhu, Ankasa Regenerative Therapeutics)

– Preceded by discovery stage research grant TR1-01249 (Dr. Longaker and Dr. Helm, Stanford)

Project: embryonic stem cell derived neural cell therapy for Huntington Disease

– Currently funded stage: IND enabling development, CLIN1-10953 (Dr. Thompson, UC Irvine)

– Preceded by preIND-enabling studies, PC1-08117 (Dr. Thompson, UC Irvine)

– Preceded by discovery stage research grant (TR2-01841) (Dr. Thompson, UC Irvine)

Project: gene-modified hematopoietic stem cells for Artemis Deficient severe combined immunodeficiency (SCID)

– Currently funded stage: Phase 1 clinical trial CLIN2-10830 (Dr. Cowan, UC San Francisco)

– Preceded by IND enabling development, CLIN1-08363 (Dr. Puck, UC San Francisco)

– Preceded by discovery stage research grant, TR3-05535  (Dr. Cowan, UC San Francisco)

Project: retinal progenitor cell therapy for retinitis pigmentosa

– Currently funded stage: Phase 2 and 2b clinical trials, CLIN2-11472, CLIN2-09698 (Dr. Klassen, JCyte, Inc.)

– Preceded by IND enabling development, DR2A-05739 (Dr. Klassen, UC Irvine)

– Preceded by discovery stage research grant, TR2-01794 (Dr. Klassen, UC Irvine)

Meet the people who are changing the future

Kristin MacDonald

Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.

I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.

Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.

That’s when you know the treatment works. At least for Rosie.

There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.

It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.

Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.

And it’s free!

You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.

We hope to see you there.

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.

CIRM-funded treatment for Cystinosis receives orphan drug designation

Dr. Stephanie Cherqui, UC San Diego

Orphan drug designation is a special status given by the Food and Drug Administration (FDA) for potential treatments of rare diseases that affect fewer than 200,000 in the U.S. This type of status can significantly help advance treatments for rare diseases by providing financial incentives in the form of tax credits towards the cost of clinical trials and prescription drug user fee waivers.

Fortunately for us, a stem cell-gene therapy approach used in a CIRM-funded clinical trial for Cystinosis has just received orphan drug designation. The trial is being conducted by Dr. Stephanie Cherqui at UC San Diego, which is an academic collaborator for AVROBIO, Inc.

Cystinosis is a rare disease that primarily affects children and young adults, and leads to premature death, usually in early adulthood.  Patients inherit defective copies of a gene called CTNS, which results in abnormal accumulation of an amino acid called cystine in all cells of the body.  This buildup of cystine can lead to multi-organ failure, with some of earliest and most pronounced effects on the kidneys, eyes, thyroid, muscle, and pancreas.  Many patients suffer end-stage kidney failure and severe vision defects in childhood, and as they get older, they are at increased risk for heart disease, diabetes, bone defects, and neuromuscular defects. 

Dr. Cherqui’s clinical trial uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective CTNS gene. The goal of this treatment is to reintroduce the corrected stem cells into the patient to give rise to blood cells that will reduce cystine buildup in affected tissues.  

In an earlier blog, we shared a story by UCSD news that featured Jordan Janz, the first patient to participate in this trial, as well as the challenges promising approaches like this one face in terms of getting financial support. Our hope is that in addition to the funding we have provided, this special designation gives additional support to what appears to be a very promising treatment for a very rare disease.

You can read the official press release from AVROBIO, Inc. related to the orphan drug designation status here.

‘A Tornado at the Front Door, a Tsunami at the Back Door’

CIRM funds a lot of research and all of it has life-saving potential. But every once in a while you come across a story about someone benefiting from CIRM-supported research that highlights why the work we do is so important. This story is about a brilliant researcher at UC San Diego developing a treatment for a really rare disease, one that was unlikely to get funding from a big pharmaceutical company because it offered little chance for a return on its investment. At CIRM we don’t have to worry about things like that. Stories like this are our return on investment.

Our thanks to our colleagues at UCSD News for allowing us to run this piece in full.

Jordan Janz and Dr. Stephanie Cherqui in her lab at the UC San Diego School of Medicine: Photo courtesy UC San Diego

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By Heather Buschman, PhD

Born with a rare disease called cystinosis, 20-year-old Jordan Janz arrived at a crossroads: continue life as-is, toward a future most likely leading to kidney failure and an early death or become the first patient in the world to undergo a new gene-and-stem cell therapy developed over more than a decade by UC San Diego School of Medicine researchers

For the majority of Jordan Janz’s 20 years of life, most neighbors in his tiny Canadian town never knew he was sick. Janz snowboarded, hunted and fished. He hung with friends, often playing ice hockey video games. He worked in shipping and receiving for a company that makes oil pumps.

But there were times when Janz was younger that he vomited up to 13 times each day. He received a growth hormone injection every day for six years. He needed to swallow 56 pills every day just to manage his symptoms. And the medication required around-the-clock administration, which meant his mother or another family member had to get up with him every night.

“I was tired for school every day,” Janz said. “I was held back in second grade because I missed so much school. And because the medication had a bad odor to it, when I did go to school kids would ask, ‘What’s that smell?’ It was hard.”

Janz was born with cystinosis, a rare metabolic disorder that’s detected in approximately one in 100,000 live births worldwide. People with cystinosis inherit a mutation in the gene that encodes a protein called cystinosin. Cystinosin normally helps cells transport the amino acid cystine. Because cells in people with cystinosis don’t produce the cystinosin protein, cystine accumulates. Over the years, cystine crystals build up and begin to damage tissues and organs, from the kidneys and liver to muscles, eyes and brain. Numerous symptoms and adverse consequences result.

These days, Janz manages his condition. There’s a time-release version of the symptom-relieving medication now that allows him to go 12 hours between doses, allowing for a good night’s sleep. But there’s no stopping the relentless accumulation of cystine crystals, no cure for cystinosis.  

In October 2019, Janz became the first patient to receive treatment as part of a Phase I/II clinical trial to test the safety and efficacy of a unique gene therapy approach to treating cystinosis. The treatment was developed over more than a decade of research by Stephanie Cherqui, PhD, associate professor of pediatrics, and her team at University of California San Diego School of Medicine.

“The day they started looking for people for the trial, my mom picked up the phone, found a number for Dr. Cherqui, called her and put my name in as a candidate,” Janz said.

Janz’s mom, Barb Kulyk, has long followed Cherqui’s work. Like many parents of children with cystinosis, Kulyk has attended conferences, read up on research and met many other families, doctors and scientists working on the condition. Kulyk says she trusts Cherqui completely. But she was understandably nervous for her son to be the first person ever to undergo a completely new therapy.

“It’s like giving birth,” she said shortly before Janz received his gene therapy. “You’re really looking forward to the outcome, but dreading the process.”

The treatment

Cherqui’s gene therapy approach involves genetical modifying the patient’s own stem cells. To do this, her team obtained hematopoietic stem cells from Janz’s bone marrow. These stem cells are the precursors to all blood cells, including both red blood cells and immune cells. The scientists then re-engineered Janz’s stem cells in a lab using gene therapy techniques to introduce a normal version of the cystinosin gene. Lastly, they reinfused Janz with his own now-cystinosin-producing cells. The approach is akin to a bone marrow transplant — the patient is both donor and recipient.

“A bone marrow transplant can be very risky, especially when you take hematopoietic stem cells from a another person. In that case, there’s always the chance the donor’s immune cells will attack the recipient’s organs, so-called graft-versus-host disease,” Cherqui explained. “It’s a great advantage to use the patient’s own stem cells.”

As is the case for other bone marrow transplants, Janz’s gene-modified stem cells are expected to embed themselves in his bone marrow, where they should divide and differentiate to all types of blood cells. Those cells are then expected to circulate throughout his body and embed in his tissues and organs, where they should produce the normal cystinosin protein. Based on Cherqui’s preclinical data, she expects the cystinosin protein will be transferred to the surrounding diseased cells. At that point, Janz’s cells should finally be able to appropriately transport cystine for disposal — potentially alleviating his symptoms.

Before receiving his modified stem cells, Janz had to undergo chemotherapy to make space in his bone marrow for the new cells. Not unexpectedly, Janz experienced a handful of temporary chemotherapy-associated side-effects, including immune suppression, hair loss and fatigue. He also had mucositis, an inflammation of mucous membranes lining the digestive tract, which meant he couldn’t talk or eat much for a few days.

Now, only three months after his transfusion of engineered stem cells, Cherqui reports that Janz is making a good recovery, though it’s still too early to see a decrease in his cystinosis-related symptoms.

“I’ve been sleeping at least 10 hours a day for the last few weeks,” Janz said. “It’s crazy, but I know my body is just working hard to, I guess, create a new ‘me.’ So it’s no wonder I’m tired. But I’m feeling okay overall.

“One of the hardest parts for me is being inactive for so long. I’m not used to doing nothing all day. But I’m taking an online course while I wait for my immune system to rebuild. And I’m getting pretty good at video games.”

Like all Phase I/II clinical trials, the current study is designed to first test the safety and tolerability of the new treatment. Janz knows the treatment might not necessarily help him.

“When we started this trial, my mom explained it like this: ‘We have a tornado at the front door and a tsunami at the back door, and we have to pick one to go through. Neither will be any fun and we don’t know what’s going to happen, but you have to believe you will make it and go.

“So we weighed the pros and cons and, basically, if I don’t do this trial now, when I’m older I might not be healthy and strong enough for it. So I decided to go for it because, even if there are consequences from the chemotherapy, if it works I could live 20 years longer than I’m supposed to and be healthy for the rest of my life. That’s worth it.”

Besides the possible benefit to himself, Janz also sees his participation in the clinical trial as a way to contribute to the tight-knit community of families with children who have cystinosis.

“I’m willing to do if it helps the kids,” he said. “Somebody has to do it. I don’t have the money to donate to scientific conferences and stuff like that, but I can do this trial.”

The trial

If the treatment continues to meet certain criteria for safety and efficacy for Janz and one other participant after three months, two more adult participants will be enrolled. Three months after that, if the treatment continues to be safe and effective, the trial might enroll two adolescent participants. To participate in the clinical trial, individuals must meet specific eligibility requirements.

Later in the trial, Cherqui and team will begin measuring how well the treatment actually works. The specific objectives include assessing the degree to which gene-modified stem cells establish themselves in  bone marrow, how they affect cystine levels and cystine crystal counts in blood and tissues.

“This trial is the first to use gene-modified hematopoietic stem cell gene therapy to treat a multi-organ degenerative disorder for which the protein is anchored in the membrane of the lysosomes, as opposed to secreted enzymes,” Cherqui said. “We were amazed when we tested this approach in the mouse model of cystinosis — autologous stem cell transplantation reversed the disease. The tissues remained healthy, even the kidneys and the eyes.”

Trial participants are closely monitored for the first 100 days after treatment, then tested again at six, nine, 12, 18 and 24 months post-gene therapy for a variety of factors, including vital signs, cystine levels in a number of organs, kidney function, hormone function and physical well-being.

“If successful in clinical trials, this approach could provide a one-time, lifelong therapy that may prevent the need for kidney transplantation and long-term complications caused by cystine buildup,” Cherqui said.

The future

For the trial participants, all of the pre-treatment tests, the treatment itself, and monitoring afterward means a lot of travel to and long stays in San Diego.

It’s tough on Kulyk and Janz. They have to fly in from Alberta, Canada and stay in a San Diego hotel for weeks at a time. Kulyk has two older adult children, as well as a 12-year-old and a seven-year-old at home. 

“I’ve missed a lot of things with my other kids, but none of them seem to hold any grudges,” she said. “They seem to be totally fine and accepting. They’re like, ‘We’re fine, mom. You go and take care of Jordan.’”

Janz is looking forward to getting back home to his friends, his dog and his job, which provided him with paid leave while he received treatment and recovers.

For Cherqui, the search for a cystinosis cure is more than just a scientific exercise. Cherqui began working on cystinosis as a graduate student more than 20 years ago. At the time, she said, it was simply a model in which to study genetics and gene therapy.

“When you read about cystinosis, it’s just words. You don’t put a face to it. But after I met all the families, met the kids, and now that I’ve seen many of them grow up, and some of them die of the disease — now it’s a personal fight, and they are my family too.”

Patients with cystinosis typically experience kidney failure in their 20s, requiring kidney dialysis or transplantation for survival. For those born with cystinosis who make it into adulthood, the average lifespan is approximately 28 years old.

“I’m optimistic about this trial because it’s something we’ve worked so hard for and now it’s actually happening, and these families have so much hope for a better treatment,” Cherqui said. “After all the years of painstaking laboratory research, we now need to move into the clinic. If this works, it will be wonderful. If it doesn’t, we will all be disappointed but a least we’ll be able to say we tried.”

Nancy Stack, who founded the Cystinosis Research Foundation after her own daughter, Natalie, was diagnosed with the disease, calls Cherqui “the rock star of our community.”

“She cares deeply about the patients and is always available to talk, to explain her work and to give us hope,” Stack said. “She said years ago that she would never give up until she found the cure — and now we are closer to a cure than ever before.” (Read more about Natalie here.)

In addition to cystinosis, Cherqui says this type of gene therapy approach could also lead to treatment advancements for other multi-organ degenerative disorders, such as Friedreich’s ataxia and Danon disease, as well as other kidney, genetic and systemic diseases similar to cystinosis.

While they wait for the long-term results of the treatment, Kulyk is cautiously hopeful.

“Moms are used to being able to fix everything for their children — kiss boo-boos make them better, make cupcakes for school, whip up Halloween costumes out of scraps, pull a coveted toy out of thin air when it has been sold out for months.

“But we have not been able to fix this, to take it away. I not only want this disease gone for my child, I want cystinosis to be nothing more than a memory for all the children and adults living with it. I know that even if and when Jordan is cured, there will still be so much work to do, in terms of regulatory approvals and insurance coverage.

“Having hope for your child’s disease to be cured is a slippery slope. We have all been there, held hope in our hands and had to let go. But, I find myself in a familiar place, holding onto hope again and this time I am not letting go.”

Video of Dr. Cherqui and Jordan Janz talking about the therapy

For more information about the Phase I/II clinical trial for cystinosis and to learn how to enroll, call 1-844-317-7836 or email alphastemcellclinic@ucsd.edu.

Cherqui’s research has been funded by the Cystinosis Research Foundation, California Institute for Regenerative Medicine (CIRM), and National Institutes of Health. She receives additional support from the Sanford Stem Cell Clinical Center and CIRM-funded Alpha Stem Cell Clinic at UC San Diego Health, and AVROBIO.

The Top CIRM Blogs of 2019

This year the most widely read blog was actually one we wrote back in 2018. It’s the transcript of a Facebook Live: “Ask the Stem Cell Team” event about strokes and stroke recovery. Because stroke is the third leading cause of death and disability in the US it’s probably no surprise this blog has lasting power. So many people are hoping that stem cells will help them recover from a stroke.

But of the blogs that we wrote and posted this year there’s a really interesting mix of topics.

The most read 2019 blog was about a potential breakthrough in the search for a treatment for type 1 diabetes (T1D).  Two researchers at UC San Francisco, Dr. Matthias Hebrok and Dr. Gopika Nair developed a new method of replacing the insulin-producing cells in the pancreas that are destroyed by type 1 diabetes. 

Dr. Matthias Hebrok
Dr. Gopika Nair

Dr. Hebrok described it as a big advance saying: “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”

It’s not too surprising a blog about type 1 diabetes was at the top. This condition affects around 1.25 million Americans, a huge audience for any potential breakthrough. However, the blog that was the second most read is the exact opposite. It is about a rare disease called cystinosis. How rare? Well, there are only around 500 children and young adults in the US, and just 2,000 worldwide diagnosed with this condition.  

It might be rare but its impact is devastating. A genetic mutation means children with this condition lack the ability to clear an amino acid – cysteine – from their body. The buildup of cysteine leads to damage to the kidneys, eyes, liver, muscles, pancreas and brain.

Dr. Stephanie Cherqui

UC San Diego researcher Dr. Stephanie Cherqui and her team are taking the patient’s own blood stem cells and, in the lab, genetically re-engineering them to correct the mutation, then returning the cells to the patient. It’s hoped this will create a new, healthy blood system free of the disease.

Dr. Cherqui says if it works, this could help not just people with cystinosis but a wide array of other disorders: “We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders.”

Sickled cells

The third most read blog was about another rare disease, but one that has been getting a lot of media attention this past year. Sickle cell disease affects around 100,000 Americans, mostly African Americans. In November the Food and Drug Administration (FDA) approved Oxbryta, a new therapy that reduces the likelihood of blood cells becoming sickle shaped and clumping together – causing blockages in blood vessels.

But our blog focused on a stem cell approach that aims to cure the disease altogether. In many ways the researchers in this story are using a very similar approach to the one Dr. Cherqui is using for cystinosis. Genetically correcting the mutation that causes the problem, creating a new, healthy blood system free of the sickle shaped blood cells.

Two other blogs deserve honorable mentions here as well. The first is the story of James O’Brien who lost the sight in his right eye when he was 18 years old and now, 25 years later, has had it restored thanks to stem cells.

The fifth most popular blog of the year was another one about type 1 diabetes. This piece focused on the news that the CIRM Board had awarded more than $11 million to Dr. Peter Stock at UC San Francisco for a clinical trial for T1D. His approach is transplanting donor pancreatic islets and parathyroid glands into patients, hoping this will restore the person’s ability to create their own insulin and control the disease.

2019 was certainly a busy year for CIRM. We are hoping that 2020 will prove equally busy and give us many new advances to write about. You will find them all here, on The Stem Cellar.

Stem Cell Agency Approves Funding for Clinical Trials Targeting Parkinson’s Disease and Blindness

The governing Board of the California Institute for Regenerative Medicine (CIRM) yesterday invested $32.92 million to fund the Stem Cell Agency’s first clinical trial in Parkinson’s disease (PD), and to support three clinical trials targeting different forms of vision loss.

This brings the total number of clinical trials funded by CIRM to 60.

The PD trial will be carried out by Dr. Krystof Bankiewicz at Brain Neurotherapy Bio, Inc. He is using a gene therapy approach to promote the production of a protein called GDNF, which is best known for its ability to protect dopaminergic neurons, the kind of cell damaged by Parkinson’s. The approach seeks to increase dopamine production in the brain, alleviating PD symptoms and potentially slowing down the disease progress.

David Higgins, PhD, a CIRM Board member and patient advocate for Parkinson’s says there is a real need for new approaches to treating the disease. In the US alone, approximately 60,000 people are diagnosed with PD each year and it is expected that almost one million people will be living with the disease by 2020.

“Parkinson’s Disease is a serious unmet medical need and, for reasons we don’t fully understand, its prevalence is increasing. There’s always more outstanding research to fund than there is money to fund it. The GDNF approach represents one ‘class’ of potential therapies for Parkinson’s Disease and has the potential to address issues that are even broader than this specific therapy alone.”

The Board also approved funding for two clinical trials targeting retinitis pigmentosa (RP), a blinding eye disease that affects approximately 150,000 individuals in the US and 1.5 million people around the world. It is caused by the destruction of light-sensing cells in the back of the eye known as photoreceptors.  This leads to gradual vision loss and eventually blindness.  There are currently no effective treatments for RP.

Dr. Henry Klassen and his team at jCyte are injecting human retinal progenitor cells (hRPCs), into the vitreous cavity, a gel-filled space located in between the front and back part of the eye. The proposed mechanism of action is that hRPCs secrete neurotrophic factors that preserve, protect and even reactivate the photoreceptors, reversing the course of the disease.

CIRM has supported early development of Dr. Klassen’s approach as well as preclinical studies and two previous clinical trials.  The US Food and Drug Administration (FDA) has granted jCyte Regenerative Medicine Advanced Therapy (RMAT) designation based on the early clinical data for this severe unmet medical need, thus making the program eligible for expedited review and approval.

The other project targeting RP is led by Dr. Clive Svendsen from the Cedars-Sinai Regenerative Medicine Institute. In this approach, human neural progenitor cells (hNPCs) are transplanted to the back of the eye of RP patients. The goal is that the transplanted hNPCs will integrate and create a protective layer of cells that prevent destruction of the adjacent photoreceptors. 

The third trial focused on vision destroying diseases is led by Dr. Sophie Deng at the University of California Los Angeles (UCLA). Dr. Deng’s clinical trial addresses blinding corneal disease by targeting limbal stem cell deficiency (LSCD). Under healthy conditions, limbal stem cells (LSCs) continuously regenerate the cornea, the clear front surface of the eye that refracts light entering the eye and is responsible for the majority of the optical power. Without adequate limbal cells , inflammation, scarring, eye pain, loss of corneal clarity and gradual vision loss can occur. Dr. Deng’s team will expand the patient’s own remaining LSCs for transplantation and will use  novel diagnostic methods to assess the severity of LSCD and patient responses to treatment. This clinical trial builds upon previous CIRM-funded work, which includes early translational and late stage preclinical projects.

“CIRM funds and accelerates promising early stage research, through development and to clinical trials,” says Maria T. Millan, MD, President and CEO of CIRM. “Programs, such as those funded today, that were novel stem cell or gene therapy approaches addressing a small number of patients, often have difficulty attracting early investment and funding. CIRM’s role is to de-risk these novel regenerative medicine approaches that are based on rigorous science and have the potential to address unmet medical needs. By de-risking programs, CIRM has enabled our portfolio programs to gain significant downstream industry funding and partnership.”

CIRM Board also awarded $5.53 million to Dr. Rosa Bacchetta at Stanford to complete work necessary to conduct a clinical trial for IPEX syndrome, a rare disease caused by mutations in the FOXP3 gene. Immune cells called regulatory T Cells normally function to protect tissues from damage but in patients with IPEX syndrome, lack of functional Tregs render the body’s own tissues and organs to autoimmune attack that could be fatal in early childhood.  Current treatment options include a bone marrow transplant which is limited by available donors and graft versus host disease and immune suppressive drugs that are only partially effective. Dr. Rosa Bacchetta and her team at Stanford will use gene therapy to insert a normal version of the FOXP3 gene into the patient’s own T Cells to restore the normal function of regulatory T Cells.

The CIRM Board also approved investing $15.80 million in four awards in the 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.

The TRAN1 Awards are summarized in the table below:

ApplicationTitleInstitutionAward Amount
TRAN1 11536Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome  UCLA $4,896,628
TRAN1 11555BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma  UCLA $3,176,805
TRAN1 11544 Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer  City of Hope $2,873,262
TRAN1 11611Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsyNeurona Therapeutics$4,848,750

“A new awakening”: One patient advocate’s fight for her daughters life

We often talk about the important role that patient advocates play in helping advance research. That was demonstrated in a powerful way last week when the CIRM Board approved almost $12 million to fund a clinical trial targeting a rare childhood disorder called cystinosis.

The award, to Stephanie Cherqui and her team at UC San Diego (in collaboration with UCLA) was based on the scientific merits of the program. But without the help of the cystinosis patient advocate community that would never have happened. Years ago the community held a series of fundraisers, bake sales etc., and used the money to help Dr. Cherqui get her research started.

That money enabled Dr. Cherqui to get the data she needed to apply to CIRM for funding to do more detailed research, which led to her award last week. There to celebrate the moment was Nancy Stack. Her testimony to the Board was a moving celebration of how long they have worked to get to this moment, and how much hope this research is giving them.

Nancy Stack is pictured in spring 2018 with her daughter Natalie Stack and husband Geoffrey Stack. (Lar Wanberg/Cystinosis Research Foundation)

Hello my name is Nancy Stack and I am the founder and president of the Cystinosis Research Foundation.  Our daughter Natalie was diagnosed with cystinosis when she was an infant. 

Cystinosis is a rare disease that is characterized by the abnormal accumulation of cystine in every cell in the body.  The build-up of cystine eventually destroys every organ in the body including the kidneys, eyes, liver, muscles, thyroid and brain.  The average age of death from cystinosis and its complications is 28 years of age.

For our children and adults with cystinosis, there are no healthy days. They take between 8-12 medications around the clock every day just to stay alive – Natalie takes 45 pills a day.  It is a relentless and devastating disease.

Medical complications abound and our children’s lives are filled with a myriad of symptoms and treatments – there are g-tube feedings, kidney transplants, bone pain, daily vomiting,  swallowing difficulties, muscle wasting, severe gastrointestinal side effects and for some blindness.   

We started the Foundation in 2003.  We have worked with and funded Dr. Stephanie Cherqui since 2006.   As a foundation, our resources are limited but we were able to fund the initial grants for Stephanie’s  Stem Cell studies. When CIRM awarded a grant to Stephanie in 2016, it allowed her to complete the studies, file the IND and as a result, we now have FDA approval for the clinical trial. Your support has changed the course of this disease. 

When the FDA approved the clinical trial for cystinosis last year, our community was filled with a renewed sense of hope and optimism.  I heard from 32 adults with cystinosis – all of them interested in the clinical trial.  Our adults know that this is their only chance to live a full life. Without this treatment, they will die from cystinosis.  In every email I received, there was a message of hope and gratitude. 

I received an email from a young woman who said this, “It’s a new awakening to learn this morning that human clinical trials have been approved by the FDA. I reiterate my immense interest to participate in this trial as soon as possible because my quality of life is at a low ebb and the trial is really my only hope. Time is running out”. 

And a mom of a 19 year old young man who wants to be the first patient in the trial wrote and said this, “On the day the trial was announced I started to cry tears of pure happiness and I thought, a mother somewhere gets to wake up and have a child who will no longer have cystinosis. I felt so happy for whom ever that mom would be….I never imagined that the mom I was thinking about could be me. I am so humbled to have this opportunity for my son to try to live disease free.

My own daughter ran into my arms that day and we cried tears of joy – finally, the hope we had clung to was now a reality. We had come full circle.  I asked Natalie how it felt to know that she could be cured and she said, “I have spent my entire life thinking that I would die from cystinosis in my 30s but now, I might live a full life and I am thinking about how much that changes how I think about my future. I never planned too far ahead but now I can”. 

As a mother, words can’t possible convey what it feels like to know that my child has a chance to live a long, healthy life free of cystinosis – I can breathe again. On behalf of all the children and adults with cystinosis, thank you for funding Dr. Cherqui, for caring about our community, for valuing our children and for making this treatment a reality.  Our community is ready to start this trial – thank you for making this happen.

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CIRM will be celebrating the role of patient advocates at a free event in Los Angeles tomorrow. It’s at the LA Convention Center and here are the details. And did I mention it’s FREE!

Tue, June 25, 2019 – 6:00 PM – 7:00 PM PDT

Petree Hall C., Los Angeles Convention Center, 1201 South Figueroa Street Los Angeles, CA 90015

And on Wednesday, USC is holding an event highlighting the progress being made in fighting diseases that destroy vision. Here’s a link to information about the event.