An Open Letter to CIRM for World Sickle Cell Day

Nancy M. Rene

Dear CIRM,

World Sickle Cell Day is this Saturday June 19th. The goal of this day is to increase knowledge of the disease and understanding of the challenges faced.

It is a day that I greet with very mixed feelings.  I’m of course extremely grateful to CIRM for the time and money spent looking for a cure.  The work of doctors, of researchers, the courage of families in the sickle cell community who are taking part in studies, and of course those of you who worked so hard for the original funding for CIRM, I applaud all of you, yet it’s hard to wait for a cure.

While I wait I worry. I worry about my friends who are not getting good care.  They are the ones who can’t find a doctor to treat them, not able to take advantage of the medications that are already approved.  They are the ones who walk into the Emergency Room hoping for knowledgeable treatment while understanding that they may be accused of being a drug seeker,  turned away in excruciating pain. They are the ones who succumb after years of poor care.

With sickle cell disease there is the same level of understanding about medical malpractice that we had of police brutality before George Floyd. We hardly remember Rodney King or Eric Garner. As a country we were aware that something was wrong but we tended to retreat in denial after each terrible headline.

That’s where we are with sickle cell disease.  We may see a heart-wrenching story and watch televised reports with interest, but after all, it’s easier to live in disbelief, to think that medical care is not that bad, rather than understand that people are being dismissed and denied treatment. We call it structural racism without understanding what that term really means.

While I wait I must acknowledge that change is coming.  We have a Sickle Cell Data Collection Project in California that helps us track healthcare for sickle cell disease. This is data that we can use to point to structural weakness and address health disparities.  NASEM, the National Academies of Science Engineering and Medicine, has published a huge report with significant suggestions for improving sickle cell care. Many scientists, researchers and advocates took part in this landmark study, detailing what has gone wrong in health care and how to improve the work. And of course we have CIRM. I am very thankful for the leadership and pioneering work of doctors Donald Kohn, Matthew Porteus, Mark Walters, and Joseph Rosenthal who are using their knowledge and experience in this fight.

When we have successful research on stem cell transplants for sickle cell disease, many of us with sickle cell family members will want to relax, but we can’t forget those who may not be able to get a curative transplant. I hope Dr Niihara at Emmaus, and Dr. Love of Global Blood Therapeutics will continue their important work finding effective treatments. We must continue this fight on all fronts.

World Sickle Cell Day will come again next year.  Let’s see what it brings.

A sickle cell grandmother,

Nancy M. René

CIRM-catalyzed spinout files for IPO to develop therapies for genetic diseases

Graphite Bio, a CIRM-catalyzed spinout from Stanford University that launched just 14 months ago has now filed the official SEC paperwork for an initial public offering (IPO). The company was formed by CIRM-funded researchers Matt Porteus, M.D., Ph.D. and Maria Grazia Roncarolo, M.D.

Six years ago, Dr. Porteus and Dr. Roncarolo, in conjunction with Stanford University, received a CIRM grant of approximately $875K to develop a method to use CRISPR gene editing technology to correct the blood stem cells of infants with X-linked severe combined immunodeficiency (X-SCID), a genetic condition that results in a weakened immune system unable to fight the slightest infection.

Recently, Dr. Porteus, in conjunction with Graphite, received a CIRM grant of approximately $4.85M to apply the CRISPR gene editing approach to correct the blood stem cells of patients with sickle cell disease, a condition that causes “sickle” shaped red blood cells. As a result of this shape, the cells clump together and clog up blood vessels, causing intense pain, damaging organs, and increasing the risk of strokes and premature death. The condition disproportionately affects members of the Black and Latin communities.

CIRM funding helped Stanford complete the preclinical development of the sickle cell disease gene therapy and it enabled Graphite to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA), one of the last steps necessary before conducting a human clinical trial of a potential therapy. Towards the end of 2020, Graphite got the green light from the FDA to conduct a trial using the gene therapy in patients with sickle cell disease.

In a San Francisco Business Times report, Graphite CEO Josh Lehrer stated that the company’s goal is to create a platform that can apply a one-time gene therapy for a broad range of genetic diseases.

CIRM funded trial may pave way for gene therapy to treat different diseases

Image Description: Jordan Janz (left) and Dr. Stephanie Cherqui (right)

According to the  National Organization for Rare Disorders (NORD), a disease is consider rare if it affects fewer than 200,000 people. If you combine the over 7,000 known rare diseases, about 30 million people in the U.S. are affected by one of these conditions. A majority of these conditions have no cure or have very few treatment options, but a CIRM funded trial (approximately $12 million) for a rare pediatric disease has showed promising results in one patient using a gene therapy approach. The hope for the field as a whole is that this proof of concept might pave the way to use gene therapy to treat other diseases.

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 that results in abnormal accumulation of cystine (hence the name cystinosis) 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 problems.  There is currently a drug treatment for cystinosis, but it only delays the progression of the disease, has severe side effects, and is expensive.

Dr. Stephane Cherqui at UC San Diego (UCSD), in partnership with AVROBIO, is conducting a clinical trial that uses a gene therapy approach to modify a patient’s own blood stem cells with a functional version of the defective gene. The corrected stem cells are then reintroduced into the patient with the hope that they will give rise to blood cells that will reduce cystine buildup in the body.  

22 year old Jordan Janz was born with cystinosis and was taking anywhere from 40 to 60 pills a day as part of his treatment. Unfortunately the medication affected his body odor, leaving him smelling like rotten eggs or stinky cheese. In 2019, Jordan was the first of three patients to participate in Dr. Cherqui’s trial and the results have been remarkable. Tests have shown that the cystine in his eyes, skin and muscle have greatly decreased. Instead of the 40-60 pills a day, he just takes vitamins and specific nutrients his body needs. What’s more is that he no longer has a problem with body odor caused by the pills he once had to take. Although it will take much more time know if Jordan was cured of the disease, he says that he feels “essentially cured”.

In an article from the Associated Press, Jordan is optimistic about his future.

“I have more of a life now. I’m going to school. I’m hoping to open up my own business one day.”

You can learn more about Jordan by watching the video below:

Although gene therapy approaches still need to be closely studied, they have enormous potential for treating patients. CIRM has funded other clinical trials that use gene therapy approaches for different genetic diseases including X-SCID, ADA-SCID, ART-SCID, X-CGD, and sickle cell disease.

New Study Shows CIRM-Supported Therapy Cures More than 95% of Children Born with a Fatal Immune Disorder

Dr. Donald B. Kohn; Photo courtesy UCLA

A study published in the New England Journal of Medicine shows that an experimental form of stem cell and gene therapy has cured 48 of 50 children born with a deadly condition called ADA-SCID.

Children with ADA-SCID, (severe combined immunodeficiency due to adenosine deaminase deficiency) lack a key enzyme that is essential for a healthy, functioning immune system. As a result, even a simple infection could prove fatal to these children and, left untreated, most will die within the first two years of life.

In the study, part of which was supported by CIRM, researchers at the University of California Los Angeles (UCLA) and Great Ormond Street Hospital (GOSH) in London took some of the children’s own blood-forming stem cells and, in the lab, corrected the genetic mutation that causes ADA-SCID. They then returned those cells to the children. The hope was that over time the corrected stem cells would create a new blood supply and repair the immune system.

In the NEJM study the researchers reported outcomes for the children two and three years post treatment.

“Between all three clinical trials, 50 patients were treated, and the overall results were very encouraging,” said Dr. Don Kohn, a distinguished professor of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “All the patients are alive and well, and in more than 95% of them, the therapy appears to have corrected their underlying immune system problems.”

Two of the children did not respond to the therapy and both were returned to the current standard-of-care therapy. One subsequently underwent a bone marrow transplant. None of the children in the study experienced serious side-effects.

“This is encouraging news for all families affected by this rare but deadly condition,” says Maria T. Millan, MD, President and CEO of CIRM. “It’s also a testament to the power of persistence. Don Kohn has been working on developing this kind of therapy for 35 years. To see it paying off like this is a remarkable testament to his skill as a researcher and determination to help these patients.”

CIRM funding helps improve immune cell therapy to combat HIV

Image description: T cell infected with HIV.
Image Credit: National Institute of Allergy and Infectious Diseases (NIAID)

In June of last year we wrote about how Dr. Scott Kitchen and his team at UCLA are engineering blood forming stem cells in order to fight HIV, a potentially deadly virus that attacks the immune system and can worsen into AIDS if left untreated. HIV causes havoc in the body by attacking T cells, a vital part of the body’s immune system that helps fight off infections and diseases.

Dr. Kitchen’s approach uses what is called Chimeric Antigen Receptor (CAR) T gene therapy. This is a type of immune therapy that involves genetically modifying the body’s own blood forming stem cells to create T cells that have the ability to fight HIV. These newly formed immune cells have the potential to not only destroy HIV-infected cells but to create “memory cells” that could provide lifelong protection from HIV infection.

Flash forward to April of this year and the results of the CIRM funded study ($1.7M) have been published in PLOS Pathogens.

Unfortunately, although the previously designed CAR T gene therapy was still able to create HIV fighting immune cells, the way the CAR T gene therapy was designed still had the potential to allow for HIV infection.

For this new study, the team modified the CAR T gene therapy such that the cells would be resistant to infection and allow for a more efficient and longer-lasting cell response against HIV than before.

While the previous approach allowed for the continuous production of new HIV-fighting T cells that persisted for more than two years, these cells are inactivated until they come across the HIV virus. The improved CAR T gene therapy engineers the body’s immune response to HIV rather than waiting for the virus to induce a response. This is similar in concept to how a vaccine prepares the immune system to respond against a virus. The new approach also creates a significant number of “memory” T cells that are capable of quickly responding to reactivated HIV. 

The hope is that these findings can influence the development of T cells that are able carry “immune system” memory with the ability to recognize and kill virus-infected or cancerous cells. 

To date, CIRM has also funded four separate clinical trials related to the treatment of HIV/AIDS totaling over $31 million.

Three UC’s Join Forces to Launch CRISPR Clinical Trial Targeting Sickle Cell Disease

Sickle shaped red blood cells

The University of California, San Francisco (UCSF), in collaboration with UC Berkeley (UCB) and UC Los Angeles (UCLA), have been given permission by the US Food and Drug Administration (FDA) to launch a first-in-human clinical trial using CRISPR technology as a gene-editing technique to cure Sickle Cell Disease.

This research has been funded by CIRM from the early stages and, in a co-funding partnership with theNational Heart, Lung, and Blood Institute under the Cure Sickle Cell initiatve, CIRM supported the work that allowed this program to gain FDA permission to proceed into clinical trials.    

Sickle Cell Disease is a blood disorder that affects around 100,000 people, mostly Black and Latinx people in the US. It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells. Normal red blood cells are round and smooth and flow easily through blood vessels. But the sickle-shaped ones are rigid and brittle and clump together, clogging vessels and causing painful crisis episodes, recurrent hospitalization, multi-organ damage and mini-strokes.    

The three UC’s have combined their respective expertise to bring this program forward.

The CRISPR-Cas9 technology was developed by UC Berkeley’s Nobel laureate Jennifer Doudna, PhD. UCLA is a collaborating site, with expertise in genetic analysis and cell manufacturing and UCSF Benioff Children’s Hospital Oakland is the lead clinical center, leveraging its renowned expertise in cord blood and marrow transplantation and in gene therapy for sickle cell disease.

The approach involves retrieving blood stem cells from the patient and, using a technique involving electrical pulses, these cells are treated to correct the mutation using CRISPR technology. The corrected cells will then be transplanted back into the patient.

Dr. Mark Walters

In a news release, UCSF’s Dr. Mark Walters, the principal investigator of the project, says using this new gene-editing approach could be a game-changer. “This therapy has the potential to transform sickle cell disease care by producing an accessible, curative treatment that is safer than the current therapy of stem cell transplant from a healthy bone marrow donor. If this is successfully applied in young patients, it has the potential to prevent irreversible complications of the disease. Based on our experience with bone marrow transplants, we predict that correcting 20% of the genes should be sufficient to out-compete the native sickle cells and have a strong clinical benefit.”

Dr. Maria T. Millan, President & CEO of CIRM, said this collaborative approach can be a model for tackling other diseases. “When we entered into our partnership with the NHLBI we hoped that combining our resources and expertise could accelerate the development of cell and gene therapies for SCD. And now to see these three UC institutions collaborating on bringing this therapy to patients is truly exciting and highlights how working together we can achieve far more than just operating individually.”

The 4-year study will include six adults and three adolescents with severe sickle cell disease. It is planned to begin this summer in Oakland and Los Angeles.

The three UCs combined to produce a video to accompany news about the trial. Here it is:

Prime Time for Rocket

Rocket Pharmaceuticals, a company that specializes in developing genetic therapies for rare childhood disorders, just got a big boost from the European Medicines Agency (EMA). They were given a Priority Medicines (PRIME) designation for their therapy for Leukocyte Adhesion Deficiency-1 (LAD-1).

CIRM is funding ($6.56 million) Rocket’s clinical trial for LAD-I, an immune disorder that leaves patients vulnerable to repeated infections that often results in death within the first two years of life. The therapy involves taking some of the child’s own blood stem cells and, in the lab, correcting the mutation that causes LAD-I, then returning those cells to the patient. Hopefully those blood stem cells then create a new, healthy blood supply and repair the immune system.

The therapy, called RP-L201, is already showing promise in the clinical trial, hence the PRIME designation. The program was set up to help speed up development and evaluation of therapies that could help patients who have limited treatment options. Getting a PRIME designation means it is considered a priority by EMA and could reach patients sooner.

In the US, Rocket has won similar recognition from the Food and Drug Administration (FDA) and has been granted Regenerative Medicine Advanced Therapy (RMAT), Rare Pediatric Disease, and Fast Track designations.

In a news release Kinnari Patel, President and Chief Operating Officer of Rocket, said the designation showed that regulators understand the urgent need to develop a therapy for patients with LAD-1. “More than half of LAD-I patients suffer with a severe variant in which mortality occurs in up to 75% of young children who don’t receive a successful bone marrow transplant by the age of two. Securing all possible accelerated designations will enable us to collaborate with both the FDA and EMA to speed the development and delivery of a potential treatment for these patients.  We look forward to sharing initial Phase 2 data from our potentially registration-enabling LAD-I trial in the second quarter of 2021.”

That trial has now completed enrolling patients (nine altogether) but their treatments are not yet complete. LAD-1 patients with severe disease have low levels of a key protein called CD18, usually less than 2%. Of the first three patients treated in this trial CD18 levels are all higher than the 4-10% threshold considered necessary for these children to survive into adulthood. Another encouraging sign is that there were no serious side effects from the therapy.

Obviously there is still a long way to go before we know if this therapy really works, but the PRIME designation – along with the similar ones in the US – are recognition that this is a very promising start.

Going the extra mile to save a patient’s life

You can tell an awful lot about a company by the people it hires and the ability it gives them to do their job in an ethical, principled way. By that measure Rocket Pharma is a pretty darn cool company.

Rocket Pharma is running a CIRM-funded clinical trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare genetic immune disorder that leaves patients vulnerable to repeated infections that often results in death within the first two years of life. The therapy involves taking some of the child’s own blood stem cells and, in the lab, correcting the mutation that causes LAD-I, then returning those cells to the patient. Hopefully those blood stem cells then create a new, healthy blood supply and repair the immune system.

So far, they have treated the majority of the nine patients in this Phase 1/2 clinical trial. Here’s the story of three of those children, all from the same family. Every patient’s path to the treatment has been uniquely challenging. For one family, it’s been a long, rough road, but one that shows how committed Rocket Pharma (Rocket) is to helping people in need.

The patient, a young girl, is from India. The family has already lost one child to what was almost certainly LAD-I, and now they faced the very real prospect of losing their daughter too. She had already suffered numerous infections and the future looked bleak. Fortunately, the team at Rocket heard about her and decided they wanted to help enroll her in their clinical trial.

Dr. Gayatri Rao, Rocket Pharmaceuticals

Dr. Gayatri Rao, the Global Program Head for the LAD-I therapy, this patient was about 6 months old when they heard about her: “She had already been in and out of the hospital numerous times so the family were really interested in enrolling the patient. But getting the family to the US was daunting.”

Over the course of several months, the team at Rocket helped navigate the complicated immigration process. Because the parents and child would need to make several trips to the US for treatment and follow-up exams they would need multiple-entry visas. “Just to get all the paper work necessary was a monumental task. Everything had to be translated because the family didn’t speak English. By the time the family flew to Delhi for their visa interview they had a dossier that filled a 3 inch binder.”  Rocket worked closely with partners in India to provide the family on-the-ground support every step of the way.  To help ensure the family received the visas they needed, Rocket also reached out to members of Congress and six members wrote in support of the family’s application.

Finally, everything fell into place. The family had the visas, all the travel arrangements were made. The Rocket team had even found an apartment near the UCLA campus where the family would stay during the treatment and stocked it with Indian food.

But on the eve of their flight to the US, the coronavirus pandemic hit. International flights were cancelled. Borders were closed. A year of work was put on hold and, more important, the little girl’s life hung in the balance.

Over the course of the next few months the little girl suffered several infections and had to be hospitalized. The family caught COVID and had to undergo quarantine till they recovered. But still the Rocket team kept working on a plan to bring them to the US. Finally, in late January, as vaccines became available and international flights opened up once again, the family were able to come to the US. One west-coast based Rocket team member even made sure that upon arriving to the apartment in UCLA, there was a home-cooked meal, a kitchen stocked with groceries, and handmade cards welcoming them to help transition the family into their new temporary “home.” They are now in living in that apartment near UCLA, waiting for the treatment to start.

Gayatri says it would have been easy to say: “this is too hard” and try to find another patient in the trial, but no one at Rocket wanted to do that: “Once a patient gets identified, we feel like we know them and the team feels invested in doing everything we can for them. We know it may not work out. But at the end of the day, we recognize that this child often has no other choices, and that motivates us to keep going despite the challenges.  If anything, this experience has taught us that with persistence and creativity, we can surmount these challenges.”

Maybe doing the right thing brings its own rewards, because this earlier this month Rocket was granted Regenerative Medicine Advanced Therapy (RMAT) designation for their treatment for LAD-I. This is a big deal because it means the therapy has already shown it appears to be safe and potentially beneficial to patients, so the designation means that if it continues to be safe and effective it may be eligible for a faster, more streamlined approval process. And that means it can get to the patients who need it, outside of a clinical trial, faster.

A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.

Scientists use stem cells to create Neanderthal-like “mini-brain”

Alysson R. Muotri, Ph.D.

The evolution of modern day humans has always been a topic that has been shrouded in mystery. Some of what is known is that Neanderthals, an archaic human species that lived on this planet up until about 11,700 years ago, interbred with our species (Homo sapiens) at some point in time. Although their brains were about as big as ours, anthropologists think they must have worked differently due to the fact that they never achieved the sophisticated technology and artistry modern humans have.

Since brains do not fossilize, it has been challenging to see how these two early human species have changed over time. To help answer this question, Dr. Alysson Muotri and his team at UC San Diego created so-called “mini-brains” using stem cells and gene editing technology to better understand how the Neanderthal brain might have functioned.

For this study, Dr. Muotri and his team closely evaluated the differences in genes between modern day humans and Neanderthals. They found a total of 61 different genes, but for this study focused on one in particular that plays a role in influencing early brain development.

Brain organoids that carry a Neanderthal gene.
Image courtesy of the Muotri Lab and UCSD

Using gene editing technology, the team introduced the Neanderthal version of the gene into human stem cells. These stem cells, which have the ability to become various cell types, were then used to create brain cells. These cells eventually formed brain organoids or “mini-brains”, 3D models made of cells that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. In a previous CIRM funded study, Dr. Muotri had used “mini-brains” to model an autism spectrum disorder and help test treatments.

Dr. Muotri and his team found that the Neanderthal-like brain organoids looked very different than modern human brain organoids, having a distinctly different shape. Upon further analysis, the team found that modern and Neanderthal-like brain organoids also differed in the way their cells grow. Additionally, the way in which connections between neurons formed as well as the proteins involved in forming these connections differed between the two organoids. Finally, electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-like brain organoids.

According to Muotri, the neural network changes in Neanderthal-like brain organoids mimic the way newborn primates acquire new abilities more rapidly than human newborns.

In a news release from UCSD, Dr. Muotri discusses the next steps in advancing this research.

“This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered. We’re looking forward to this new combination of stem cell biology, neuroscience and paleogenomics.”

The full results of this study were published in Science.