Adrienne Shapiro and Marissa Cors are a remarkable pair by any definition. The mother and daughter duo share a common bond, and a common goal. And they are determined not to let anyone stop them achieving that goal.
Marissa was born with sickle cell disease (SCD) a life-threatening genetic condition where normally round, smooth red blood cells are instead shaped like sickles. These sickle cells are brittle and can clog up veins and arteries, blocking blood flow, damaging organs, and increasing the risk of strokes. It’s a condition that affects approximately 100,000 Americans, most of them Black.
Adrienne became a patient advocate, founding Axis Advocacy, after watching Marissa get poor treatment in hospital Emergency Rooms. Marissa often talks about the way she is treated like a drug-seeker simply because she knows what medications she needs to help control excruciating pain on her Sickle Cell Experience Live events on Facebook.
Now the two are determined to ensure that no one else has to endure that kind of treatment. They are both fierce patient advocates, vocal both online and in public. And we recently got a chance to sit down with them for our podcast, Talking ‘Bout (re) Generation. These ladies don’t pull any punches.
Yesterday the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $8.39 million to the University of California, San Francisco (UCSF) to fund a clinical trial for sickle cell disease (SCD). An additional $51.08 million was awarded to fifteen community colleges and universities across California to fund undergraduate and master’s level programs that will help train the next generation of stem cell researchers.
SCD is an inherited blood disorder caused by a single gene mutation that changes a single base in the B globin gene leading to the production of defective hemoglobin that polymerizes and damages red blood cells thus the “sickle” shaped red blood cells. The damaged cells cause blood vessels to occlude/close up and that can lead to multiple organ damage as well as reduced quality of life and life expectancy.
Mark Walters, M.D., and his team at UCSF Benioff Children’s Hospital Oakland will be conducting a clinical trial that uses CRISPR-Cas9 gene editing technology to correct the genetic mutation in the blood stem cells of patients with severe SCD. The corrected blood stem cells will then be reintroduced back into patients with the goal of correcting the defective hemoglobin and thus producing functional, normal shaped red blood cells.
This clinical trial will be eligible for co-funding under the landmark agreement between CIRM and the National Heart, Lung, and Blood Institute (NHLBI) of the NIH. The CIRM-NHLBI agreement is intended to co-fund cell and gene therapy programs under the NHLBI’s “Cure Sickle Cell” initiative. The goal is to markedly accelerate the development of cell and gene therapies for SCD. CIRM has previously funded the preclinical development of this therapy through a Translational award as well as its IND-enabling studies through a Late Stage Preclinical award in partnership with NHLBI.
The CIRM Bridges to Stem Cell Research and Therapy program provides undergraduate and master’s students with the opportunity to take stem cell related courses and receive hands on experience and training in a stem cell research related laboratory at a university or biotechnology company. Fifteen institutions received a total of $51.08 million to carry out these programs to train the next generation of scientists.
The awards are summarized in the table below.
Bridges to Stem Cell Research and Therapy at Pasadena City College
Pasadena City College
CIRM Bridges to Stem Cell Research and Therapy Training Grant
CSU San Marcos
Bridges to Stem Cell Research Internship Program
San Diego State University
CIRM Bridges 3.0
CIRM Regenerative Medicine and Stem Cell Research Biotechnology Training Program
CSU Long Beach
Stem Cell Internships in Laboratory-based Learning (SCILL) continue to expand the scientific workforce for stem cells research and therapies.
San Jose State University
Strengthening the Pipeline of Master’s-level Scientific and Laboratory Personnel in Stem Cell Research
CIRM Bridges Science Master’s Program
San Francisco State University
CIRM Graduate Student Training in Stem Cell Sciences in the Stem Cell Technology and Lab Management Emphasis of the MS Biotechnology Program
CSU Channel Islands
CSUN CIRM Bridges 3.0 Stem Cell Research & Therapy Training Program
Stem Cell Scholars: a workforce development pipeline, educating, training and engaging students from basic research to clinical translation.
CSU San Bernardino
Training Master’s Students to Advance the Regenerative Medicine Field
Cal Poly San Luis Obispo
Building Career Pathways into Stem Cell Research and Therapy Development
City College of San Francisco
Bridges to Stem Cell Research and Therapy: A Talent Development Program for Training Diverse Undergraduates for Careers in Regenerative Medicine
CIRM Bridges to Stem Cell Research and Therapy
Berkeley City College
“We are pleased to fund a promising trial for sickle cell disease that uses the Nobel Prize winning gene editing technology CRISPR-Cas9,” says Maria T. Millan, M.D., President and CEO of CIRM. “This clinical trial is a testament to how the CIRM model supports promising early-stage research, accelerates it through translational development, and advances it into the clinics. As the field advances, we must also meet the demand for promising young scientists. The CIRM Bridges programs across the state of California will provide students with the tools and resources to begin their careers in regenerative medicine.”
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.
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.
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.
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.
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:
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.
Have you ever been at a party where someone says “hey, I’ve got a good idea” and then before you know it everyone in the room is adding to it with ideas and suggestions of their own and suddenly you find yourself with 27 pages of notes, all of them really great ideas. No, me neither. At least, not until yesterday when we held the first meeting of our Scientific Strategy Advisory Panel.
This is a group that was set up as part of Proposition 14, the ballot initiative that refunded CIRM last November (thanks again everyone who voted for that). The idea was to create a panel of world class scientists and regulatory experts to help guide and advise our Board on how to advance our mission. It’s a pretty impressive group too. You can see who is on the SSAP here.
The meeting involved some CIRM grantees talking a little about their work but mostly highlighting problems or obstacles they considered key issues for the future of the field as a whole. And that’s where the ideas and suggestions really started flowing hard and fast.
It started out innocently enough with Dr. Amander Clark of UCLA talking about some of the needs for Discovery or basic research. She advocated for a consortium approach (this quickly became a theme for many other experts) with researchers collaborating and sharing data and findings to help move the field along.
She also called for greater diversity in research, including collecting diverse cell samples at the basic research level, so that if a program advanced to later stages the findings would be relevant to a wide cross section of society rather than just a narrow group.
Dr. Clark also said that as well as supporting research into neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there needed to be a greater emphasis on neurological conditions such as autism, bipolar disorder and other mental health problems.
(CIRM is already committed to both increasing diversity at all levels of research and expanding mental health research so this was welcome confirmation we are on the right track).
Dr. Mike McCun called for CIRM to take a leadership role in funding fetal tissue research, things the federal government can’t or won’t support, saying this could really help in developing an understanding of prenatal diseases.
Dr. Christine Mummery, President of ISSCR, advocated for support for early embryo research to deepen our understanding of early human development and also help with issues of infertility.
Then the ideas started coming really fast:
There’s a need for knowledge networks to share information in real-time not months later after results are published.
We need standardization across the field to make it easier to compare study results.
We need automation to reduce inconsistency in things like feeding and growing cells, manufacturing cells etc.
Equitable access to CRISPR gene-editing treatments, particularly for underserved communities and for rare diseases where big pharmaceutical companies are less likely to invest the money needed to develop a treatment.
Do a better job of developing combination therapies – involving stem cells and more traditional medications.
One idea that seemed to generate a lot of enthusiasm – perhaps as much due to the name that Patrik Brundin of the Van Andel Institute gave it – was the creation of a CIRM Hotel California, a place where researchers could go to learn new techniques, to share ideas, to collaborate and maybe take a nice cold drink by the pool (OK, I just made that last bit up to see if you were paying attention).
The meeting was remarkable not just for the flood of ideas, but also for its sense of collegiality. Peter Marks, the director of the Food and Drug Administration’s Center for Biologics Evaluation and Research (FDA-CBER) captured that sense perfectly when he said the point of everyone working together, collaborating, sharing information and data, is to get these projects over the finish line. The more we work together, the more we will succeed.
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future.Today we feature a blog written by two of our fabulous Discovery and Translation team Science Officers, Dr. Kent Fitzgerald and Dr. Ross Okamura.
If you believe that you can know a person by their deeds, the partnership opportunities offered by CIRM illustrate what we, as an agency, believe is the most effective way to deliver on our mission statement, accelerating regenerative medicine treatments to patients with unmet medical needs.
In our past, we have offered awards covering basic biology projects which in turn provided the foundation to produce promising therapies to ease human suffering. But those are only the first steps in an elaborate process.
In order to bring these potential therapies to the clinic, selected drug candidates must next go through a set of activities designed to prepare them for review by the Food and Drug Administration (FDA). For cell therapies, the first formal review is often the Pre- Investigational New Drug Application Consultation or pre-IND. This stage of drug development is commonly referred to as Translational, bridging the gap between our Discovery or early stage research and Clinical Trial programs.
One of our goals at CIRM is to prepare Translational projects we fund for that pre-IND meeting with the FDA, to help them gather data that support the hope this approach will be both safe and effective in patients. Holding this meeting with the FDA is the first step in the often lengthy process of conducting FDA regulated clinical trials and hopefully bringing an approved therapy to patients.
What type of work is required for a promising candidate to move from the Discovery stage into FDA regulated development? To address the needs of Translational science, CIRM offers the Translational Research Project funding opportunity. Activities that CIRM supports at the Translational stage include:
Process Development to allow manufacturing of the candidate therapy under Good Manufacturing Practices (GMP). This is to show that they can manufacture at a large enough scale to treat patients.
Assay development and qualification of measurements to determine whether the drug is being manufactured safely while retaining its curative properties.
Studies to determine the optimal dose and the best way to deliver that dose.
Pilot safety studies looking how the patient might respond after treatment with the drug.
The development of a clinical plan indicating under what rules and conditions the drug might be prescribed to a patient.
These, and other activities supported under our Translational funding program, all help to inform the FDA when they consider what pivotal studies they will require prior to approving an Investigational New Drug (IND) application, the next step in the regulatory approval process.
Since CIRM first offered programs specifically aimed at addressing the Translational stage of therapeutic candidates we have made 41 awards totaling approximately $150 million in funding. To date, 13 have successfully completed and achieved their program goals, while 19 others are still actively working towards meeting their objective. Additionally, three (treating Spina Bifida, Osteonecrosis, and Sickle Cell Disease) of the 13 programs have gone on to receive further CIRM support through our Clinical Stage programs.
During our time administering these awards, CIRM has actively partnered with our grantees to navigate what is required to bring a therapy from the bench to the bedside. CIRM operationalizes this by setting milestones that provide clear definitions of success, specific goals the researchers have to meet to advance the project and also by providing resources for a dedicated project manager to help ensure the project can keep the big picture in mind while executing on their scientific progress.
Throughout all this we partner with the researchers to support them in every possible way. For example, CIRM provides the project teams with Translational Advisory Panels (TAPs, modeled after the CIRM’s Clinical Advisory Panels) which bring in outside subject matter experts as well as patient advocates to help provide additional scientific, regulatory and clinical expertise to guide the development of the program at no additional cost to the grantees. One of the enduring benefits that we hope to provide to researchers and organizations is a practical mastery of translational drug development so that they may continue to advance new and exciting therapies to all patients.
Through CIRM’s strong and continued support of this difficult stage of development, CIRM has developed an internal practical expertise in advancing projects through Translation. We employ our experience to guide our awardees so they can avoid common pitfalls in the development of cell and gene therapies. The end goal is simple, helping to accelerate their path to the clinic and fulfilling the mission of CIRM that has been twice given to us by the voters of California, bringing treatments to patients suffering from unmet medical needs.
Last November Marissa Cors, a patient advocate in the fight against Sickle Cell Disease (SCD), told the Stem Cellar “A stem cell cure will end generations of guilt, suffering, pain and early death. It will give SCD families relief from the financial, emotional and spiritual burden of caring someone living with SCD. It will give all of us an opportunity to have a normal life. Go to school, go to work, live with confidence.” With each passing month it seems we are getting closer to that day.
CIRM is funding four clinical trials targeting SCD and another project we are supporting has just been given the green light by the Food and Drug Administration to start a clinical trial. Clearly progress is being made.
Yesterday we got a chance to see that progress. We held a Zoom event featuring Marissa Cors and other key figures in the fight against SCD, CIRM Science Officer Dr. Ingrid Caras and Evie Junior. Evie is a pioneer in this struggle, having lived with sickle cell all his life but now hoping to live his life free of the disease. He is five months past a treatment that holds out the hope of eradicating the distorted blood cells that cause such devastation to people with the disease.
You can listen to his story, and hear about the other progress being made. Here’s a recording of the Zoom event.