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 rare treat, an interview with Moderna’s Dr. Derrick Rossi.
Moderna co-founder Dr. Derrick Rossi
It’s not often you get a chance to sit down with one of the key figures in the fight against the coronavirus and get to pick his brain about the best ways to beat it. We were fortunate enough to do that on Wednesday, talking to Dr. Derrick Rossi, the co-founder of Moderna, about the vaccine his company has developed.
CIRM’s President and CEO, Dr. Maria Millan, was able to chat to Dr. Rossi for one hour about his background (he got support from CIRM in his early post-doctoral research at Stanford) and how he and his colleagues were able to develop the COVID-19 vaccine, how the vaccine works, how effective it is, how it performs against new variations of the virus.
He also told us what he would have become if this science job hadn’t worked out.
All in all it was a fascinating conversation with someone whose work is offering a sense of hope for millions of people around the world.
If you missed it first time around you can watch it here.
The left image represents a microscopic view of the bone marrow of a myeloma-bearing mouse treated with control, and the right image represents the same for a myeloma-bearing mouse treated with ION251, an experimental therapeutic. The red dots represent the IRF4 protein within human myeloma cells, which are much sparser after ION251 treatment. Image credit: UC San Diego Health
Multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020. Unfortunately, many patients with this type of blood cancer eventually develop resistance to multiple types of treatments. This phenomenon is partially due to the fact that cancer stem cells, which have the ability to evade traditional therapies and then self-renew, help drive the disease.
It is for this reason that a team of researchers, at the UC San Diego School of Medicine and Ionis Pharmaceuticals, are developing a therapy that can destroy these malignant stem cells, thereby preventing the cancer from coming back. With support from CIRM, the team developed an approach that interacts with IRF4, a gene that allows myeloma stem cells and tumor cells to grow and survive chemotherapy and radiation. They have engineered an oligonucleotide, a short DNA molecule, to prevent IRF4 from functioning. The therapy, known as ION251, lowered disease burden, reduced the amount of myeloma stem cells, and increased survival when tested in mice bearing human myeloma. These results have enabled the team to start a Phase I clinical trial to see if this approach is safe and effective in people with myeloma.
To study the disease and test ION251, the team transplanted human myeloma cells into mice that lack an immune system and thus won’t reject human cells. Ten mice received the ION251 treatment and an additional ten mice received a control treatment. After receiving the ION251 therapy, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. Additionally, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did.
In a news release from UC San Diego Health, Dr. Leslie Crews, co-senior author and assistant professor at the UCSD School of Medicine, elaborated on the promising results from the mouse study.
“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank — in the treated mice, we couldn’t find any myeloma cells left for us to study. It makes the science more difficult, but it gives me hope for patients.”
The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information on this can be viewed by clicking the link here.
The full results of this study were published in the journal Cell Stem Cell.
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.
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.
Dr. Kent Fitzgerald
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.
Dr. Derrick Rossi might be the most famous man whose name you don’t recognize. Dr. Rossi is the co-founder of Moderna. Yes, that Moderna. The COVID-19 vaccine Moderna. The vaccine that in clinical trials proved to be around 95 percent effective against the coronavirus.
Dr. Rossi also has another claim to fame. He is a former CIRM scholar. He did some of his early research, with our support, in the lab of Stanford’s Dr. Irv Weissman.
So how do you go from a lowly post doc doing research in what, at the time, was considered a rather obscure scientific field, to creating a company that has become the focus of the hopes of millions of people around the world? Well, join us on Wednesday, January 27th at 9am (PST) to find out.
CIRM’s President and CEO, Dr. Maria Millan, will hold a live conversation with Dr. Rossi and we want you to be part of it. You can join us to listen in, and even post questions for Dr. Rossi to answer. Think of the name dropping credentials you’ll get when say to your friends; “Well, I asked Dr. Rossi about that and he told me…..”
Dr. Yanhong Shi (left) and Dr. Vaithilingaraja Arumugaswami (right)
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 focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.
It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19. In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus. One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.
It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grantand $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center. The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.
At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain. Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.
The team first created neurons and astrocytes. Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them. The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients. The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.
Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain. They were able to create two different organoid models: one that contained astrocytes and one without them. They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model.
The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2. They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient. Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4. Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral. The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.
The results were astounding. The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes. Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes.
“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”
In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes. They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death. For neurons, it was able to rescue them from steadily losing their function and even dying.
The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19. Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after.
“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami. “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”
The full results to this study were published in Cell Stem Cell.
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.
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 have a guest blog by CIRM Senior Science Officer Lisa Kadyk, outlining how she and her colleagues actively search for the best science to fund.
Lisa Kadyk, Ph.D.
Hi everyone,
This is Lisa Kadyk, a Science Officer from the CIRM Therapeutics team, here to tell you about some of the work our team does to support the CIRM mission of accelerating stem cell treatments to patients with unmet medical needs. Our job involves seeking out and recruiting great scientists to apply to CIRM and supporting those we fund.
Therapeutics team members manage both the awards that fund the final preclinical studies required before testing a therapeutic in a clinical trial (CLIN1), and the awards that fund the clinical trials themselves (CLIN2).
I mentioned above that we actively recruit new applicants for our CLIN1 and CLIN2 awards – which is not an activity that is typical of most funding agencies – so why and how do we do this?
It all comes down to our mission of accelerating the development of therapies to help patients with unmet medical needs. It turns out that there are many potential applicants developing cutting edge therapies who don’t know much or anything about CIRM, and the ways we can help them with getting those therapies to the clinic and through clinical trials. So, to bridge this gap, we Science Officers attend scientific conferences, read the scientific literature and meet regularly with each other to stay abreast of new therapeutic approaches being developed in both academia and industry, with the goal of identifying and reaching out to potential applicants about what CIRM has to offer.
What are some of the things we tell potential applicants about how partnering with CIRM can help accelerate their programs? First of all, due to the efforts of a very efficient Review team, CIRM is probably the fastest in the business for the time between application and potential funding. It can be as short as three months for a CLIN1 or CLIN2 application to be reviewed by the external Grants Working Group and approved by the CIRM Board, whereas the NIH (for example) estimates it takes seven to ten months to fund an application. Second, we have frequent application deadlines (monthly for CLIN1 and CLIN2), so we are always available when the applicant is ready to apply. Third, we have other accelerating mechanisms in place to help grantees once they’ve received funding, such as the CIRM Alpha Stem Cell Clinics network of six clinical sites throughout California (more efficient clinical trial processes and patient recruitment) and Clinical Advisory Panels (CAPs) – that provide technical, clinical or regulatory expertise as well as patient advocate guidance to the grantee. Finally, we Science Officers do our best to help every step of the way, from application through grant closeout.
We now feel confident that our recruitment efforts, combined with CIRM’s more efficient funding pipeline and review processes, are accelerating development of new therapies. Back in 2016, a new CIRM Strategic Plan included the goal of recruiting 50 successful (i.e., funded) clinical trial applicants within five years. This goal seemed like quite a stretch, since CIRM had funded fewer than 20 clinical trials in the previous ten years. Fast-forward to the end of 2020, and CIRM had funded 51 new trials in those five years, for a grand total of 68 trials.
Now, with the passage of Proposition 14 this past November, we are looking forward to bringing more cell and gene therapeutic candidates into clinical trials. If you are developing one yourself, feel free to let us know… or don’t be surprised if you hear from us!
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 look at a way of making blood stem cell transplants safer and more readily available
Unfortunately, there is still a certain degree of risk that accompanies this procedure. Before a blood stem cell transplant can be performed, diseased or defective blood stem cells in the patient’s bone marrow need to be removed using chemotherapy or radiation to make room for the transplant. This leaves the patient temporarily without an immune system and at risk for a life-threatening viral infection. Additionally, viral infections pose a serious risk to patients with immune deficiency disorders, with viruses accounting upwards of 40% of deaths in these patients.
That’s why in October 2017, the CIRM ICOC Board awarded $4.8M to fund a clinical trial conducted by Dr. Michael Pulsipher at the Children’s Hospital of Los Angeles. Dr. Pulsipher and his team are using virus-specific T cells (VSTs), a special type of cell that plays an important role in the immune response, to treat immunosuppressed or immune deficient patients battling life-threatening viral infections. This trial includes patients with persistent viral infections after having received a blood stem cell transplant as well as those with immune deficiency disorders that have not yet received a blood stem cell transplant. The VSTs used in this trial specifically treat cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus infections. They are manufactured using cells from healthy donors and are banked so as to be readily available when needed.
One challenge of receiving a stem cell transplant can be finding a patient and donor that are a close or identical match. This is done by looking at specific human leukocyte antigens (HLA), which are protein molecules we inherit from our parents. To give you an idea of how challenging this can be, you only have a 25% chance of being an HLA identical match with your sibling.
Because VSTs are temporary soldiers that are administered to fight the viral infection and then disappear, Dr. Pulsipher and his team are using partially HLA-matched VSTs to treat patients in their trial. Previous studies have indicated that partially HLA-matched T-cells can be effective in treating patients. The availability of partially HLA-matched VST banks that can be used “off the shelf” improves accessibility and shortens the time for patients to receive VST therapy, which will save lives.
To learn more about Dr. Pulsipher’s work, please view the video below:
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 take a deeper dive into CIRM’s Alpha Stem Cell Clinics Network. The following is written by Dr. Geoff Lomax, Senior Officer of CIRM Therapeutics and Strategic Infrastructure.
The year 2014 has been described as the regenerative medicine renaissance: the European Union approved its first stem cell-based therapy and the FDA authorized ViaCyte’s CIRM funded clinical trial for diabetes. A path forward for stem cell treatments had emerged and there was a growing pipeline of products moving towards the clinic. At the time, many in the field came to recognize the need for clinical trial sites with the expertise to manage this growing pipeline. Anticipating this demand, CIRM’s provided funding for a network of medical centers capable of supporting all aspect of regenerative medicine clinical trials. In 2015, the Alpha Stem Cell Clinics Network was launched to for this purpose.
The Alpha Clinics Network is comprised of leading California medical centers with specific expertise in delivering patient-centered stem cell and gene therapy treatments. UC San Diego, City of Hope, UC Irvine and UC Los Angeles were included in the initial launch, and UC San Francisco and UC Davis entered the network in 2017. Between 2015 and 2020 these sites supported 105 regenerative medicine clinical trials. Twenty-three were CIRM-funded clinical trials and the remaining 82 were sponsored by commercial companies or the Alpha Clinic site. These trials are addressing unmet medical needs for almost every disease where regenerative medicine is showing promise including blindness, blood disorders (e.g. sickle cell disease) cancer, diabetes, HIV/AIDS, neurological diseases among others.
As of spring of 2020 the network had inked over $57 million in contracts with commercial sponsors. High demand for Alpha Clinics reflects the valuable human and technical resources they provide clinical trial sponsors. These resources include:
Skilled patient navigators to educate patients and their families about stem cell and gene therapy treatments and assist them through the clinical trial process.
Teams and facilities specialized in the manufacturing and/or processing of patients’ treatments. In some instances, multiple Alpha Clinic sites collaborate in manufacturing and delivery of a personalized treatment to the patient.
Nurses and clinicians with experience with regenerative medicine and research protocols to effectively deliver treatments and subsequently monitor the patients.
The multi- site collaborations are an example of how the network operates synergistically to accelerate the development of new treatments and clinical trials. For example, the UC San Francisco Alpha Clinic is collaborating with UC Berkeley and the UC Los Angeles Alpha Clinic to develop a CIRM-funded gene therapy for sickle cell disease. Each partner brings a unique expertise to the program that aims to correct a genetic mutilation in the patients’ blood stem cells to effectively cure the disease. Most recently, City of Hope has partnered with UC Irvine and UC San Diego as part of CIRM’s COVID-19 research program to study how certain immune system antibodies might be used as a treatment for respiratory disease in infected patients. In another COVID-19 study, UC Irvine and UC Davis are working with a commercial sponsor to evaluate a treatment for infected adults.
The examples above are a small sample of the variety of collaborations CIRM funding has enabled. As the Alpha Clinics track record grown, sponsors are increasingly coming to California to enable the success of their research programs. Sponsors with trials running across the country have noted a desire to expand their number of Alpha Clinic sties because they consistently perform at the highest level.
Back in 2014, it was hard to imagine over one hundred clinical trials would be served by the CIRM network in just five years. Fortunately, CIRM was able to draw on the knowledge of its internal team, external advisors and the ICOC to anticipate this need and provide California infrastructure to rise to the occasion.
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the people of California 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.
Dr. John Zaia, City of Hope stem cell researcher
The news that effective vaccines have been developed to help fight COVID-19 was a truly bright spot at the end of a very dark year. But it will be months, in some countries years, before we have enough vaccines to protect everyone. That’s why it’s so important to keep pushing for more effective ways to help people who get infected with the virus.
One of those ways is in a clinical study that CIRM is funding with City of Hope’s Dr. John Zaia. Dr. Zaia and his team, in partnership with the Translational Genomics Research Institute (TGen) in Flagstaff, Arizona, are using something called convalescent plasma to try and help people who have contracted the virus. Here’s the website they have created for the study.
Plasma is a part of our blood that carries proteins, called antibodies, that help defend our bodies against viral infections. When a patient recovers from COVID-19, their blood plasma contains antibodies against the virus. The hope is that those antibodies can now be used as a potential treatment for COVID-19 to help people who are newly infected.
For the study to succeed they’ll first need people who have recovered from the virus to donate blood. That’s particularly appropriate in January because this is National Volunteer Blood Donor Month.
The team has three elements to their approach:
A rapid-response screening program to screen potential COVID-19 convalescent plasma donors, particularly in underserved communities.
A laboratory center that can analyze the anti-SARS-CoV-2 antibodies properties in COVID-19 convalescent plasma.
An analysis of the clinical course of the disease in COVID-19 patients to identify whether antibody properties correlate with clinical benefit of COVID-19 convalescent plasma.
There’s reason to believe this approach might work. A study published this week in the New England Journal of Medicine, found that blood plasma from people who have recovered from COVID-19 can help older adults and prevent them from getting seriously ill with the virus if they get the plasma within a few days of becoming infected.
We are used to thinking of blood donations as being used to help people after surgery or who have been in an accident. In this study the donations serve another purpose, but one that is no less important. The World Health Organization describes blood as “the most precious gift that anyone can give to another person — the gift of life. A decision to donate your blood can save a life, or even several if your blood is separated into its components — red cells, platelets and plasma.”
That plasma could help in developing more effective treatments against the virus. Because until we have enough vaccines for everyone, we are still going to need as much help as we can get in fighting COVID-19. The recent surge in cases throughout the US and Europe are a reminder that this virus is far from under control. We have already lost far too many people. So, if you have recently recovered from the virus, or know someone who has, consider donating blood to this study. It could prove to be a lifesaver.
For more information about the study and how you can be part of it, click here.
The Stem Cellar 