Tomorrow, February 28th, is Rare Disease Day. It’s a day to remind ourselves of the millions of people, and their families, struggling with these diseases. These conditions are also called orphan diseases because, in many cases, drug companies were not interested in adopting them to develop treatments.
Here at the California Institute for Regenerative Medicine (CIRM), we understand the importance of funding research that impacts not just the most common diseases. In fact, 50% of all the projects we fund target a rare disease or condition such as: Retinitis pigmentosa, Sickle cell disease, Huntington’s disease, and Duchenne Muscular Dystrophy.
Over the years, CIRM has invested millions of dollars in helping children born with severe combined immunodeficiency (SCID), including $12 million to test a newly designed therapy in a clinical trial at UC San Francisco.
Children born with SCID have no functioning immune system so even a simple infection can prove life-threatening or fatal. We recently shared an update from one of the young patients in the trial.
Additionally, last December, the CIRM governing Board awarded $4,048,253 to Dr. Joseph Anderson and his team at UC Davis to develop a blood stem cell gene therapy for the treatment of Tay-Sachs disease.
Tay-Sachs disease is a rare genetic disorder where a deficiency in the Hex A gene results in excessive accumulation of certain fats in the brain and nerve cells and causes progressive dysfunction.
There are several forms of Tay-Sachs disease, including an infant, juvenile, and adult forms. Over a hundred mutations in the disease-causing Hex A gene have been identified that result in enzyme disfunction. There are currently no effective therapies or cures for Tay-Sachs.
The irony of rare diseases is that a lot of people have them. The total number of Americans living with a rare disease is estimated at between 25-30 million. Two-thirds of these patients are children.
Right now, individual disease programs tend to try individual approaches to developing a treatment, which is time consuming and expensive. That’s why this past summer, CIRM signed a Memorandum of Understanding (MOU) with the Foundation for the National Institutes of Health (FNIH) to join the Bespoke Gene Therapy Consortium (BGTC).
BGTC is a public-private partnership, managed by FNIH, that brings together the National Institutes of Health (NIH), the U.S. Food and Drug Administration (FDA), and multiple public and private sector organizations to streamline the development and delivery of gene therapies for rare diseases.
“At CIRM we have funded several projects using gene therapy to help treat, and even cure, people with rare diseases such as severe combined immunodeficiency,” says Dr. Maria T. Millan, the President and CEO of CIRM. “But even an agency with our resources can only do so much. This agreement with the Bespoke Gene Therapy Consortium will enable us to be part of a bigger partnership, one that can advance the field, overcome obstacles and lead to breakthroughs for many rare diseases.”
CIRM is proud to fund and spread awareness of rare diseases and invites you to watch this video about how they affect families around the world.
Let’s back up a little. Children born with SCID have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life. Several of the approaches CIRM has funded use the child’s own blood stem cells to help fix the problem. But at Jasper Therapeutics they are using another approach. They use a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s own blood supply with one that is free of the SCID mutation, which helps restore their immune system.
However, there’s a problem. Most bone marrow transplants use chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. It can be effective, but it is also toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
To get around that problem Jasper Therapeutics is using an antibody called JSP191 – developed with CIRM funding – that directs the patient’s own immune cells to kill diseased blood stem cells, creating room to transplant new, healthy cells. To date the therapy has already been tested in 16 SCID patients.
In addition to treating 16 patients treated without any apparent problems, Jasper has also been granted Fast Track Designation by the US Food and Drug Administration. This can help speed up the review of treatments that target serious unmet conditions. They’ve also been granted both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.
In a news release, Ronald Martell, President and CEO of Jasper Therapeutics said:
“The FDA’s Fast Track designation granted for JSP191 in Severe Combined Immunodeficiency (SCID) reinforces the large unmet medical need for patients with this serious disease. Along with its previous designations of Orphan and Rare Pediatric Disease for JSP191, the FDA’s Fast Track recognizes JSP191’s potential role in improving clinical outcomes for SCID patients, many of whom are too fragile to tolerate the toxic chemotherapy doses typically used in a transplant.”
For children born with severe combined immunodeficiency (SCID) life can be very challenging. SCID means they have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life.
There are stem cell/gene therapies funded by the California Institute for Regenerative Medicine (CIRM), such as ones at UCLA and UCSF/St. Judes, but an alternative method of treating, and even curing the condition, is a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s blood supply with one that is free of the SCID mutation, which helps restore their immune system.
However, current HCT methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
To change that, Dr. Judy Shizuru at Stanford University, with CIRM funding, developed an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells, creating the room needed to transplant new, healthy cells. The goal was to make stem cell transplants safer and more effective for the treatment of many life-threatening blood disorders.
That approach, JSP191, is now being championed by Jasper Therapeutics and they just got some very good news from the Food and Drug Administration (FDA). The FDA has granted JSP191 Fast Track Designation, which can speed up the review of therapies designed to treat serious conditions and fill unmet medical needs.
In a news release, Ronald Martell, President and CEO of Jasper Therapeutics, said this is good news for the company and patients: “This new Fast Track designation recognizes the potential role of JSP191 in improving clinical outcomes for these patients and will allow us to more closely work with the FDA in the upcoming months to determine a path toward a Biologics License Application (BLA) submission.”
Getting a BLA means Jasper will be able to market the antibody in the US and make it available to all those who need it.
This is the third boost from the FDA for Jasper. Previously the agency granted JSP191 both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.
For years scientists have been touting the potential of CRISPR, a gene editing tool that allows you to target a specific mutation and either cut it out or replace it with the corrected form of the gene. But like all new tools it had its limitations. One important one was the difficult in delivering the corrected gene to mature cells in large numbers.
Scientists at the Gladstone Institutes and U.C. San Francisco say they think they have found a way around that. And the implications for using this technique to develop new therapies for deadly diseases are profound.
In the past scientists used inactivated viruses as a way to deliver corrected copies of the gene to patients. We have blogged about UCLA’s Dr. Don Kohn using this approach to treat children born with SCID, a deadly immune disorder. But that was both time consuming and expensive.
CRISPR, on the other hand, showed that it could be easier to use and less expensive. But getting it to produce enough cells for an effective therapy proved challenging.
The team at Gladstone and UCSF found a way around that by switching from using CRISPR to deliver a double-stranded DNA to correct the gene (which is toxic to cells in large quantities), and instead using CRISPR to deliver a single stranded DNA (you can read the full, very technical description of their approach in the study they published in the journal Nature Biotechnology).
Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and the senior author of the study, said this more than doubled the efficiency of the process. “One of our goals for many years has been to put lengthy DNA instructions into a targeted site in the genome in a way that doesn’t depend on viral vectors. This is a huge step toward the next generation of safe and effective cell therapies.”
It has another advantage too, according to Gladstone’s Dr. Jonathan Esensten, an author of the study. “This technology has the potential to make new cell and gene therapies faster, better, and less expensive.”
The team has already used this method to generate more than one billion CAR-T cells – specialized immune system cells that can target cancers such as multiple myeloma – and says it could also prove effective in targeting some rare genetic immune diseases.
When Hataalii Begay was born in a remote part of the Navajo nation he was diagnosed with a rare, usually fatal condition. Today, thanks to a therapy developed at UCSF and funded by CIRM, he’s a normal healthy four year old boy running around in cowboy boots.
That stem cell therapy could now help save the lives of other children born with this deadly immune disorder because it has been granted fast-track review status by the US Food and Drug Administration (FDA).
The disorder is Artemis-SCID, a form of severe combined immunodeficiency disease. Children born with this condition have no functioning immune system so even a simple infection can prove life-threatening or fatal.
Currently, the only approved treatment for Artemis-SCID is a bone-marrow transplant, but many children are unable to find a healthy matched donor for that procedure. Even when they do find a donor they often need regular injections of immunoglobulin to boost their immune system.
In this clinical trial, UCSF Doctors Mort Cowan and Jennifer Puck are using the patient’s own blood stem cells, taken from their bone marrow. In the lab, the cells are modified to correct the genetic mutation that causes Artemis-SCID and then re-infused back into the patients. The goal is that over the course of several months these cells will create a new blood supply, one that is free of Artemis-SCID, and that will in turn help repair the child’s immune system.
So far the team has treated ten newly-diagnosed infants and three older children who failed transplants. Dr. Cowan says early data from the trial is encouraging. “With gene therapy, we are seeing these babies getting older. They have normal T-cell immunity and are getting immunized and vaccinated. You wouldn’t know they had any sort of condition if you met them; it’s very heartening.”
Because of that encouraging data, the FDA is granting this approach Regenerative Medicine Advanced Therapy (RMAT) designation. RMAT is a fast-track designation that can help speed up the development, review and potential approval of treatments for serious or life-threatening diseases.
“This is great news for the team at UCSF and in particular for the children and families affected by Artemis-SCID,” says Dr. Maria T. Millan, the President and CEO of CIRM. “The RMAT designation means that innovative forms of cell and gene therapies like this one may be able to accelerate their route to full approval by the FDA and be available to all the patients who need it.”
Advanced stem cell research and therapy development for more than 75 diseases.
Funded 76 clinical trials with 3,200+ patients enrolled.
Helped cure over 40 children of fatal immunological disorders with gene-modified cell therapies.
One of these patients is Ronnie, who just days after being born was diagnosed with severe combined immunodeficiency (SCID), a rare immune disorder that is often fatal within two years.
Fortunately, doctors told his parents about a CIRM-funded clinical trial conducted by UC San Francisco and St. Jude Children’s Hospital. Doctors took some of Ronnie’s own blood stem cells and, in the lab, corrected the genetic mutation that caused the condition. They then gave him a mild dose of chemotherapy to clear space in his bone marrow for the corrected cells to be placed and to grow. Over the next few months, the blood stem cells created a new blood supply and repaired Ronnie’s immune system. He is now a happy, healthy four-year-old boy who loves going to school with other children.
Another patient, Evie Junior, is pioneering the search for a cure for sickle cell disease: a painful, life-threatening condition.
In July of 2020, Evie took part in a CIRM-funded clinical trial where his own blood stem cells were genetically modified to overcome the disease-causing mutation. Those cells were returned to him, and the hope is they’ll create a sickle cell-free blood supply. Evie hasn’t had any crippling bouts of pain or had to go to the hospital since his treatment.
To demonstrate treatment efficacy, study investigators will continue to monitor the recovery of Evie, Ronnie, and others who participate in clinical trials.
CIRM’s new strategic plan seeks to help real life patients like Ronnie and Evie by optimizing its clinical trial funding partnership model to advance more therapies to FDA for approval.
In addition, CIRM will develop ways to overcome manufacturing hurdles for the delivery of regenerative medicine therapies and create Community Care Centers of Excellence that support diverse patient participation in the rapidly maturing regenerative medicine landscape. Stay tuned as we cover these goals here on The Stem Cellar.
Often on the Stem Cellar we feature CIRM-funded work that is helping advance the field, unlocking some of the secrets of stem cells and how best to use them to develop promising therapies. But every once in a while it’s good to remind ourselves that this work, while it may often seem slow, is already saving lives.
Meet Ja’Ceon Golden. He was one of the first patients treated at U.C. San Francisco, in partnership with St. Jude Children’s Hospital in Memphis, as part of a CIRM-funded study to treat a rare but fatal disorder called Severe Combined Immunodeficiency (SCID). Ja’Ceon was born without a functioning immune system, so even a simple cold could have been fatal.
At UCSF a team led by Dr. Mort Cowan, took blood stem cells from Ja’Ceon and sent them to St. Jude where another team corrected the genetic mutation that causes SCID. The cells were then returned to UCSF and re-infused into Ja’Ceon.
Over the next few months those blood stem cells grew in number and eventually helped heal his immune system.
He recently came back to UCSF for more tests, just to make sure everything is OK. With him, as she has been since his birth, was his aunt and guardian Dannie Hawkins. She says Ja’Ceon is doing just fine, that he has just started pre-K, is about to turn five years old and in January will be five years post-therapy. Effectively, Ja’Ceon is cured.
SCID is a rare disease, there are only around 70 cases in the US every year, but CIRM funding has helped produce cures for around 60 kids so far. A recent study in the New England Journal of Medicine showed that a UCLA approach cured 95 percent of the children treated.
The numbers are impressive. But not nearly as impressive, or as persuasive of the power of regenerative medicine, as Ja’Ceon and Dannie’s smiles.
When someone scores a goal in soccer all the attention is lavished on them. Fans chant their name, their teammates pile on top in celebration, their agent starts calling sponsors asking for more money. But there’s often someone else deserving of praise too, that’s the player who provided the assist to make the goal possible in the first place. With that analogy in mind, CIRM just provided a very big assist for a very big goal.
The goal was scored by Jasper Therapeutics. They have just announced data from their Phase 1 clinical trial treating people with Myelodysplastic syndromes (MDS). This is a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and leads to low numbers of normal blood cells, especially red blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.
The most effective way to treat, and even cure, MDS/AML is with a blood stem cell transplant, but this is often difficult for older patients, because it involves the use of toxic chemotherapy to destroy their existing bone marrow blood stem cells, to make room for the new, healthy ones. Even with a transplant there is often a high rate of relapse, because it’s hard for chemotherapy to kill all the cancer cells.
Jasper has developed a therapy, JSP191, which is a monoclonal antibody, to address this issue. JSP191 helps supplement the current treatment regimen by clearing all the remaining abnormal cells from the bone marrow and preventing relapse. In addition it also means the patients gets smaller doses of chemotherapy with lower levels of toxicity. In this Phase 1 study six patients, between the ages of 65 and 74, were given JSP191 – in combination with low-dose radiation and chemotherapy – prior to getting their transplant. The patients were followed-up at 90 days and five of the six had no detectable levels of MDS/AML, and the sixth patient had reduced levels. None of the patients experienced serious side effects.
Clearly that’s really encouraging news. And while CIRM didn’t fund this clinical trial, it wouldn’t have happened without us paving the way for this research. That’s where the notion of the assist comes in.
CIRM support led to the development of the JSP191 technology at Stanford. Our CIRM funds were used in the preclinical studies that form the scientific basis for using JSP191 in an MDS/AML setting.
Not only that, but this same technique was also used by Stanford’s Dr. Judy Shizuru in a clinical trial for children born with a form of severe combined immunodeficiency, a rare but fatal immune disorder in children. A clinical trial that CIRM funded.
It’s a reminder that therapies developed with one condition in mind can often be adapted to help treat other similar conditions. Jasper is doing just that. It hopes to start clinical trials this year using JSP191 for people getting blood stem cell transplants for severe autoimmune disease, sickle cell disease and Fanconi anemia.
At CIRM we are modest enough to know that we can’t do everything by ourselves. To succeed we need partners. And in UC Davis we have a terrific partner. The work they do in advancing stem cell research is exciting and really promising. But it’s not just the science that makes them so special. It’s also their compassion and commitment to caring for patients.
What follows is an excerpt from an article by Lisa Howard on the work they do at UC Davis. When you read it you’ll see why we are honored to be a part of this research.
Gene therapy research at UC Davis
UC Davis’ commitment to stem cell and gene therapy research dates back more than a decade.
In 2010, with major support from the California Institute for Regenerative Medicine (CIRM), UC Davis launched the UC Davis Institute for Regenerative Cures, which includes research facilities as well as a Good Manufacturing Practice (GMP) facility.
Led by Jan Nolta, a professor of cell biology and human anatomy and the director of the UC Davis Institute for Regenerative Cures, the new center leverages UC Davis’ network of expert researchers, facilities and equipment to establish a center of excellence aimed at developing lifelong cures for diseases.
Nolta began her career at the University of Southern California working with Donald B. Kohn on a cure for bubble baby disease, a condition in which babies are born without an immune system. The blood stem cell gene therapy has cured more than 50 babies to date.
Work at the UC Davis Gene Therapy Center targets disorders that potentially can be treated through gene replacement, editing or augmentation.
“The sectors that make up the core of our center stretch out across campus,” said Nolta. “We work with the MIND Institute a lot. We work with the bioengineering and genetics departments, and with the Cancer Center and the Center for Precision Medicine and Data Sciences.”
A recent UC Davis stem cell study shows a potential breakthrough for healing diabetic foot ulcers with a bioengineered scaffold made up of human mesenchymal stem cells (MSCs). Another recent study revealed that blocking an enzyme linked with inflammation enables stem cells to repair damaged heart tissue. A cell gene therapy study demonstrated restored enzyme activity in Tay-Sachs disease affected cells in humanized mouse models.
“Some promising and exciting research right now at the Gene Therapy Center comes from work with hematopoietic stem cells and with viral vector delivery,” said Nolta.
Hematopoietic stem cells give rise to other blood cells. A multi-institutional Phase I clinical trial using hematopoietic stem cells to treat HIV-lymphoma patients is currently underway at UC Davis.
“We are genetically engineering a patient’s own blood stem cells with genes that block HIV infection,” said Joseph Anderson, an associate professor in the UC Davis Department of Internal Medicine. The clinical trial is a collaboration with Mehrdad Abedi, the lead principal investigator.
“When the patients receive the modified stem cells, any new immune system cell, like T-cell or macrophage, that is derived from one of these stem cells, will contain the HIV-resistant genes and block further infection,” said Anderson.
He explained that an added benefit with the unique therapy is that it contains an additional gene that “tags” the stem cells. “We are able to purify the HIV-resistant cells prior to transplantation, thus enriching for a more protective cell population.
Kyle David Fink
Kyle David Fink, an assistant professor of neurology at UC Davis, is affiliated with the Stem Cell Program and Institute for Regenerative Cures. His lab is focused on leveraging institutional expertise to bring curative therapies to rare, genetically linked neurological disorders.
“We are developing novel therapeutics targeted to the underlying genetic condition for diseases such as CDKL5 deficiency disorder, Angelman, Jordan and Rett syndromes, and Juvenile Huntington’s disease,” said Fink.
The lab is developing therapies to target the underlying genetic condition using DNA-binding domains to modify gene expression in therapeutically relevant ways. They are also creating novel delivery platforms to allow these therapeutics to reach their intended target: the brain.
“The hope is that these highly innovative methods will speed up the progress of bringing therapies to these rare neurodegenerative disease communities,” said Fink.
Jasmine Carter, a graduate research assistant at the UC Davis Stem Cell Program, October 18, 2019. (AJ Cheline/UC Davis)
Developing potential lifetime cures
Among Nolta’s concerns is how expensive gene therapy treatments can be.
“Some of the therapies cost half a million dollars and that’s simply not available to everyone. If you are someone with no insurance or someone on Medicare, which reimburses about 65 percent, it’s harder for you to get these life-saving therapies,” said Nolta.
To help address that for cancer patients at UC Davis, Nolta has set up a team known as the “CAR T Team.”
Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy in which a patient’s own immune cells are reprogrammed to attack a specific protein found in cancer cells.
“We can develop our own homegrown CAR T-cells,” said Nolta. “We can use our own good manufacturing facility to genetically engineer treatments specifically for our UC Davis patients.”
Although safely developing stem cell treatments can be painfully slow for patients and their families hoping for cures, Nolta sees progress every day. She envisions a time when gene therapy treatments are no longer considered experimental and doctors will simply be able to prescribe them to their patients.
“And the beauty of the therapy is that it can work for the lifetime of a patient,” said Nolta.
Brenden Whittaker was born with a rare genetic disorder called X-linked chronic granulomatous disease (X-CGD). This condition affects the immune system’s ability to fight off common germs, specifically bacteria and fungi, and can result in infections that would only be mild for healthy people. Unfortunately for Brenden, he has suffered life-threatening infections that have required him to be hospitalized hundreds of times throughout most of his childhood. At only 16 years old, he got a very bad case of pneumonia that resulted in having tissue from his right lung removed. By age 22, the treatments he had received to fight off infections had stopped working entirely.
His prognosis looked grim, but fortunately he was informed of a CIRM-funded clinical trial conducted by Dr. Don Kohn to treat his condition. He would go on to become the first participant in this trial, which involved taking his blood stem cells, using gene therapy to correct the X-CGD mutation, and reintroducing these modified cells back into his body. Following his treatment, blood tests confirmed that the treatment produced enough corrected cells for Brenden to now be protected from severe infection.
Before the CIRM-funded treatment, the chances of severe infection were virtually everywhere, something many of us might better understand given everything going on with COVID-19. But now with a new lease on life, Brenden is giving back to the very community that helped him in his time of need. He is currently working as a patient care associate at his local hospital in Ohio. Considered an essential worker, Brenden’s responsibilities include taking patients’ vital signs, helping them eat and get cleaned up, and going for walks around the unit with those who are able to do so. He also plans to attend nursing school in the future.
In a news release, Brenden talks about wanting to give back to those in similar situations as him and demonstrates true selflessness.
“My job entails doing anything I can to make a patient’s time in the hospital a little bit easier while at the same time helping the doctors and nurses monitor for any new health developments. From the nurses who sat with me holding my hand and telling me about their lives when I was up in the middle of the night with a fever, to the patient transporters who remembered my name and talked with me the whole way to surgery, to the doctors who wouldn’t give up until they found an option that worked for me, these people are the reason the hospital setting is the only place I want to work. If I can help even one person the way these people have helped me, I will be happy.”
In addition to Brenden, five additional patients who received the same treatment for X-CGD are also doing well. This same gene therapy approach for blood stem cells was used in another CIRM-funded trial for SCID, another kind of genetic immune disorder. The SCID trial resulted in over 50 babies being cured of the condition, including little Evie, who is featured on the cover of CIRM’s 18-month report.