Anyone who knows anything about CIRM knows about Bob Klein. He’s the main author and driving force behind both Proposition 71 and Proposition 14, the voter-approved ballot initiatives that first created and then refunded CIRM. It’s safe to say that without Bob there’d be no CIRM.
Recently we had the great good fortune to sit down with Bob to chat about the challenges of getting a proposition on the ballot in a time of pandemic and electoral pandemonium, what he thinks CIRM’s biggest achievements are (so far) and what his future plans are.
Yesterday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved $8.5 million to continue funding of the Summer Program to Accelerate Regenerative Medicine Knowledge (SPARK) and Alpha Stem Cell Clinics (ASCC).
This past February, the Board approved continued funding for stem cell focused educational programs geared towards undergraduate, masters, pre/postdoctoral, and medical students. The SPARK program is an existing CIRM educational program that provides for a summer internship for high school students.
To continue support for SPARK, the Board has approved $5.1 million to be allocated to ten new awards ($509,000 each) with up to a five-year duration to support 500 trainees. The funds will enable high school students all across California to directly take part in summer research at various institutions with a stem cell, gene therapy, or regenerative medicine focus. The goal of these programs is to prepare and inspire the next generation of scientists and provide opportunities for California’s diverse population, including those who might not have the opportunity to take part in summer research internships due to socioeconomic constraints.
CIRM’s ASCC Network is a unique regenerative medicine-focused clinical trial network that currently consists of five medical centers across California who specialize in accelerating stem cell and gene-therapy clinical trials by leveraging of resources to promote efficiency, sharing expertise, and enhancing chances of success for the patients. To date, over 105 trials in various disease indications have been supported by the ASCC Network. While there are plans being developed for a significant ASCC Network expansion by some time next year, funding for all five sites has ended or are approaching the end of their current award period. To maintain the level of activity of the ASCC Network until expansion funding is available next year, the Board approved $3.4 million to be allocated to five supplemental awards (up to $680,000 each) in order to provide continued funding to all five sites; the host institutions will be required to match the CIRM award. These funds will support talent retention and program key activities such as the coordination of clinical research, management of patient and public inquiries, and other operational activities vital to the ASCC Network.
“Education and infrastructure are two funding pillars critical for creating the next generation of researchers and conducting stem cell based clinical trials” says Maria T. Millan, M.D., President and CEO of CIRM. “The importance of these programs was acknowledged in Proposition 14 and we expect that they will continue to be important components of CIRM’s programs and strategic direction in the years to come.”
The Board also awarded $14.5 million to fund three translational stage research projects (TRAN1), whose goal is to support early development activities necessary for advancement to a clinical study or broad end use of a potential therapy.
The awards are summarized in the table below:
Development of novel synNotch CART cell therapy in patients with recurrent EGFRvIII+ glioblastoma
CAR-Tnm cell therapy for melanoma targeting TYRP-1
HSC-Engineered Off-The-Shelf CAR-iNKT Cell Therapy for Multiple Myeloma
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.
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 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.
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.
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.We kick off this event with a letter from our the Chair of our Board, Jonathan Thomas.
When voters approved Proposition 14 last November, they gave the Stem Cell Agency a new lease on life and a chance to finish the work we began with the approval of Proposition 71 in 2004. It’s a great honor and privilege. It’s also a great responsibility. But I think looking back at what we have achieved over the last 16 years shows we are well positioned to seize the moment and take CIRM and regenerative medicine to the next level and beyond.
When we started, we were told that if we managed to get one project into a clinical trial by the time our money ran out we would have done a good job. As of this moment we have 68 clinical trials that we have funded plus another 31 projects in clinical trials where we helped fund crucial early stage research. That inexorable march to therapies and cures will resume when we take up our first round of Clinical applications under Prop 14 in March.
But while clinical stage projects are the end game, where we see if therapies really work and are safe in people, there’s so much more that we have achieved since we were created. We have invested $900 million in basic research, creating a pipeline of the most promising stem cell research programs, as well as investing heavily on so-called “translational” projects, which move projects from basic science to where they’re ready to apply to the Food and Drug Administration (FDA) to begin clinical trials.
We have funded more than 1,000 projects, with each one giving us valuable information to help advance the science. Our funding has helped attract some of the best stem cell scientists in the world to California and, because we only fund research in California, it has persuaded many companies to either move here or open offices here to be eligible for our support. We have helped create the Alpha Stem Cell Clinics, a network of leading medical centers around the state that have the experience and expertise to deliver stem cell therapies to patients. All of those have made California a global center in the field.
That result is producing big benefits for the state. An independent Economic Impact Analysis reported that by the end of 2018 we had already helped generate an extra $10.7 billion in new sales revenue and taxes for California, hundreds of millions more in federal taxes and created more than 56,000 new jobs.
Used our support for stem cell research to leverage an additional $12 billion in private funding for the field.
Enrolled more than 2700 patients in CIRM funded clinical trials
In many ways our work is just beginning. We have laid the groundwork, helped enable an extraordinary community of researchers and dramatically accelerated the field. Now we want to get those therapies (and many more) over the finish line and get them approved by the FDA so they can become available to many more people around the state, the country and the world.
We also know that we have to make these therapies available to all people, regardless of their background and ability to pay. We have to ensure that underserved communities, who were often left out of research in the past, are an integral part of this work and are included in every aspect of that research, particularly clinical trials. That’s why we now require anyone applying to us for funding to commit to engaging with underserved communities and to have a written plan to show how they are going to do that.
Over the coming month, you will hear more about some of the remarkable things we have managed to achieve so far and get a better sense of what we hope to do in the future. We know there will be challenges ahead and that not everything we do or support will work. But we also know that with the team we have built at CIRM, the brilliant research community in California and the passion and drive of the patient advocate community we will live up to the responsibility the people of California placed in us when they approved Proposition 14.
Since the first grant was issued in April 2006, CIRM has funded a wide range of research conducted by top scientists at UCLA for a wide range of diseases. To give a retrospective look at all the research, UCLA released a news article that describes all this work up until this past September. During this period, UCLA researchers were awarded 120 grants totaling more than $307 million. We’ll highlight some of these findings from the article below.
51 Basic Biology CIRM Grants
Basic biology research encompasses very early stage work that focuses on the very essentials such as how stem cells work, how to successfully turn a stem cell into another type of cell, and other basic mechanisms that underly the stem cell research field. This research is critical because they inform future therapies for dozens of conditions including heart disease, genetic and blood disorders, cancer, spinal cord injuries and neurological disorders.
3 Consecutive Year-Long CIRM Training Grants
These CIRM grants are essential in training the next generation of scientists and physicians in the regenerative medicine field. The CIRM training grants supported 146 graduate students, post‐doctoral fellows, and clinical fellows working in UCLA laboratories by providing them year-long training fellowships. This program was so successful that the UCLA Broad Stem Cell Research Center funded 26 additional fellowships to supplement CIRM’s support.
5 COVID-19 Related Grants
Shortly after the coronavirus pandemic, CIRM authorized $5 million in emergency funding to fund COVID-19 related projects. UCLA has received a $1.02 million to support four discovery research projects and one translational project. Discovery research promotes promising new technologies that could be translated to enable broad use and improve patient care. Translational research takes it a step further by promoting the activities necessary for advancement to clinical study of a potential therapy.
1 Alpha Stem Cell Clinic (ASCC) Grant
One award was used to establish the UCLA‐UCI Alpha Stem Cell Clinic. It is one of five leading medical centers throughout California that make up the CIRM ASSC Network, which specializes in the delivery of stem cell therapies by providing world-class, state of the art infrastructure to support clinical research.
COVID-19 and social and racial injustice are two of the biggest challenges facing the US right now. This Thursday, October 8th, we are holding a conversation that explores finding answers to both.
The CIRM Alpha Stem Cell Clinic Network Symposium is going to feature presentations about advances in stem cell and regenerative research, highlighting treatments that are already in the clinic and being offered to patients.
But we’re also going to dive a little deeper into the work we support, and use it to discuss two of the most pressing issues of the day.
One of the topics being featured is research into COVID-19. To date CIRM has funded 17 different projects, including three clinical trials. We’ll talk about how these are trying to find ways to help people infected with the virus, seeing if stem cells can help restore function to organs and tissues damaged by the virus, and if we can use stem cells to help develop safe and effective vaccines.
Immediately after that we are going to use COVID-19 as a way of exploring how the people most at risk of being infected and suffering serious consequences, are also the ones most likely to be left out of the research and have most trouble accessing treatments and vaccines.
Study after study highlights how racial and ethnic minorities are underrepresented in clinical trials and disproportionately affected by debilitating diseases. We have a responsibility to change that, to ensure that the underserved are given the same opportunity to take part in clinical trials as other communities.
How do we do that, how do we change a system that has resisted change for so long, how do we overcome the mistrust that has built up in underserved communities following decades of abuse? We’ll be talking about with experts who are on the front lines of this movement.
It promises to be a lively meeting. We’d love to see you there. It’s virtual – of course – it’s open to everyone, and it’s free.
What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.
Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.
The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?
It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.
We’ll hear what’s being done to find therapies for
Rare diseases that affect children
Type 1 diabetes
We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.
It’s going to be a fascinating day. And did I mention it’s free!
On December 12th we hosted our latest ‘Facebook Live: Ask the Stem Cell Team’ event. This time around we really did mean team. We had a host of our Science Officers answering questions from friends and supporters of CIRM. We got a lot of questions and didn’t have enough time to address them all. So here’s answers to all the questions.
What are the obstacles to using partial cellular reprogramming to return people’s entire bodies to a youthful state.Paul Hartman. San Leandro, California
Dr. Kelly Shepard: Certainly, scientists have observed that various manipulations of cells, including reprogramming, partial reprogramming, de-differentiation and trans-differentiation, can restore or change properties of cells, and in some cases, these changes can reflect a more “youthful” state, such as having longer telomeres, better proliferative capacity, etc. However, some of these same rejuvenating properties, outside of their normal context, could be harmful or deadly, for example if a cell began to grow and divide when or where it shouldn’t, similar to cancer. For this reason, I believe the biggest obstacles to making this approach a reality are twofold: 1) our current, limited understanding of the nature of partially reprogrammed cells; and 2) our inability to control the fate of those cells that have been partially reprogrammed, especially if they are inside a living organism. Despite the challenges, I think there will be step wise advances where these types of approaches will be applied, starting with specific tissues. For example, CIRM has recently funded an approach that uses reprogramming to make “rejuvenated” versions of T cells for fighting lung cancer. There is also a lot of interest in using such approaches to restore the reparative capacity of aged muscle. Perhaps some successes in these more limited areas will be the basis for expanding to a broader use.
What’s going on with Stanford’s stem cell trials for stroke? I remember the first trial went really well In 2016 have not heard anything about since? Elvis Arnold
Dr. Lila Collins: Hi Elvis, this is an evolving story. I believe you are referring to SanBio’s phase 1/2a stroke trial, for which Stanford was a site. This trial looked at the safety and feasibility of SanBio’s donor or allogeneic stem cell product in chronic stroke patients who still had motor deficits from their strokes, even after completing physical therapy when natural recovery has stabilized. As you note, some of the treated subjects had promising motor recoveries.
SanBio has since completed a larger, randomized phase 2b trial in stroke, and they have released the high-level results in a press release. While the trial did not meet its primary endpoint of improving motor deficits in chronic stroke, SanBio conducted a very similar randomized trial in patients with stable motor deficits from chronic traumatic brain injury (TBI). In this trial, SanBio saw positive results on motor recovery with their product. In fact, this product is planned to move towards a conditional approval in Japan and has achieved expedited regulatory status in the US, termed RMAT, in TBI which means it could be available more quickly to patients if all goes well. SanBio plans to continue to investigate their product in stroke, so I would stay tuned as the work unfolds.
Also, since you mentioned Stanford, I should note that Dr Gary Steinberg, who was a clinical investigator in the SanBio trial you mentioned, will soon be conducting a trial with a different product that he is developing, neural progenitor cells, in chronic stroke. The therapy looks promising in preclinical models and we are hopeful it will perform well for patients in the clinic.
I am a stroke survivor will stem cell treatment able to restore my motor skills?Ruperto
Dr. Lila Collins:
Hi Ruperto. Restoring motor loss after stroke is a very active area of research. I’ll touch upon a few ongoing stem cell trials. I’d just like to please advise that you watch my colleague’s comments on stem cell clinics (these can be found towards the end of the blog) to be sure that any clinical research in which you participate is as safe as possible and regulated by FDA.
Back to stroke, I mentioned SanBio’s ongoing work to address motor skill loss in chronic stroke earlier. UK based Reneuron is also conducting a phase 2 trial, using a neural progenitor cell as a candidate therapy to help recover persistent motor disability after stroke (chronic). Dr Gary Steinberg at Stanford is also planning to conduct a clinical trial of a human embryonic stem cell-derived neuronal progenitor cell in stroke.
There is also promising work being sponsored by Athersys in acute stroke. Athersys published results from their randomized, double blinded placebo controlled Ph2 trial of their Multistem product in patients who had suffered a stroke within 24-48 hours. After intravenous delivery, the cells improved a composite measure of stroke recovery, including motor recovery. Rather than acting directly on the brain, Multistem seems to work by traveling to the spleen and reducing the inflammatory response to a stroke that can make the injury worse.
Athersys is currently recruiting a phase 3 trial of its Multistem product in acute stroke (within 1.5 days of the stroke). The trial has an accelerated FDA designation, called RMAT and a special protocol assessment. This means that if the trial is conducted as planned and it reaches the results agreed to with the FDA, the therapy could be cleared for marketing. Results from this trial should be available in about two years.
Questions from several hemorrhagic stroke survivors who say most clinical trials are for people with ischemic strokes. Could stem cells help hemorrhagic stroke patients as well?
Dr. Lila Collins:
Regarding hemorrhagic stroke, you are correct the bulk of cell therapies for stroke target ischemic stroke, perhaps because this accounts for the vast bulk of strokes, about 85%.
That said, hemorrhagic strokes are not rare and tend to be more deadly. These strokes are caused by bleeding into or around the brain which damages neurons. They can even increase pressure in the skull causing further damage. Because of this the immediate steps treating these strokes are aimed at addressing the initial bleeding insult and the blood in the brain.
While most therapies in development target ischemic stroke, successful therapies developed to repair neuronal damage or even some day replace lost neurons, could be beneficial after hemorrhagic stroke as well.
I had an Ischemic stroke in 2014, and my vision was also affected. Can stem cells possibly help with my vision issues. James Russell
Dr. Lila Collins:
Hi James. Vision loss from stroke is complex and the type of loss depends upon where the stroke occurred (in the actual eye, the optic nerve or to the other parts of the brain controlling they eye or interpreting vision). The results could be:
Visual loss from damage to the retina
You could have a normal eye with damage to the area of the brain that controls the eye’s movement
You could have damage to the part of the brain that interprets vision.
You can see that to address these various issues, we’d need different cell replacement approaches to repair the retina or the parts of the brain that were damaged.
Replacing lost neurons is an active effort that at the moment is still in the research stages. As you can imagine, this is complex because the neurons have to make just the right connections to be useful.
Is there any stem cell therapy for optical nerve damage? Deanna Rice
Dr. Ingrid Caras: There is currently no proven stem cell therapy to treat optical nerve damage, even though there are shady stem cell clinics offering treatments. However, there are some encouraging early gene therapy studies in mice using a virus called AAV to deliver growth factors that trigger regeneration of the damaged nerve. These studies suggest that it may be possible to restore at least some visual function in people blinded by optic nerve damage from glaucoma
I read an article about ReNeuron’s retinitis pigmentosa clinical trial update. In the article, it states: “The company’s treatment is a subretinal injection of human retinal progenitors — cells which have almost fully developed into photoreceptors, the light-sensing retinal cells that make vision possible.” My question is: If they can inject hRPC, why not fully developed photoreceptors?Leonard
Dr. Kelly Shepard: There is evidence from other studies, including from other tissue types such as blood, pancreas, heart and liver, that fully developed (mature) cell types tend not to engraft as well upon transplantation, that is the cells do not establish themselves and survive long term in their new environment. In contrast, it has been observed that cells in a slightly less “mature” state, such as those in the progenitor stage, are much more likely to establish themselves in a tissue, and then differentiate into more mature cell types over time. This question gets at the crux of a key issue for many new therapies, i.e. what is the best cell type to use, and the best timing to use it.
My question for the “Ask the Stem Cell Team” event is: When will jCyte publish their Phase IIb clinical trial results. Chris Allen
Dr. Ingrid Caras: The results will be available sometime in 2020.
I understand the hRPC cells are primarily neurotropic (rescue/halt cell death); however, the literature also says hRPC can become new photoreceptors. My questions are:Approximately what percentage develop into functioning photoreceptors? And what percentage of the injected hRPC are currently surviving?Leonard Furber, an RP Patient
Dr. Kelly Shepard: While we can address these questions in the lab and in animal models, until there is a clinical trial, it is not possible to truly recreate the environment and stresses that the cells will undergo once they are transplanted into a human, into the site where they are expected to survive and function. Thus, the true answer to this question may not be known until after clinical trials are performed and the results can be evaluated. Even then, it is not always possible to monitor the fate of cells after transplantation without removing tissues to analyze (which may not be feasible), or without being able to transplant labeled cells that can be readily traced.
Dr. Ingrid Caras – Although the cells have been shown to be capable of developing into photoreceptors, we don’t know if this actually happens when the cells are injected into a patient’s eye. The data so far suggest that the cells work predominantly by secreting growth factors that rescue damaged retinal cells or even reverse the damage. So one possible outcome is that the cells slow or prevent further deterioration of vision. But an additional possibility is that damaged retinal cells that are still alive but are not functioning properly may become healthy and functional again which could result in an improvement in vision.
What advances have been made using stem cells for the treatment of Type 2 Diabetes?Mary Rizzo
Dr. Ross Okamura: Type 2 Diabetes (T2D) is a disease where the body is unable to maintain normal glucose levels due to either resistance to insulin-regulated control of blood sugar or insufficient insulin production from pancreatic beta cells. The onset of disease has been associated with lifestyle influenced factors including body mass, stress, sleep apnea and physical activity, but it also appears to have a genetic component based upon its higher prevalence in certain populations.
Type 1 Diabetes (T1D) differs from T2D in that in T1D patients the pancreatic beta cells have been destroyed by the body’s immune system and the requirement for insulin therapy is absolute upon disease onset rather than gradually developing over time as in many T2D cases. Currently the only curative approach to alleviate the heavy burden of disease management in T1D has been donor pancreas or islet transplantation. However, the supply of donor tissue is small relative to the number of diabetic patients. Donor islet and pancreas transplants also require immune suppressive drugs to prevent allogenic immune rejection and the use of these drugs carry additional health concerns. However, for some patients with T1D, especially those who may develop potentially fatal hypoglycemia, immune suppression is worth the risk.
To address the issue of supply, there has been significant activity in stem cell research to produce insulin secreting beta cells from pluripotent stem cells and recent clinical data from Viacyte’s CIRM funded trial indicates that implanted allogeneic human stem cell derived cells in T1D patients can produce circulating c-peptide, a biomarker for insulin. While the trial is not designed specifically to cure insulin-dependent T2D patients, the ability to produce and successfully engraft stem cell-derived beta cells would be able to help all insulin-dependent diabetic patients.
It’s also worth noting that there is a sound scientific reason to clinically test a patient-derived pluripotent stem cell-based insulin-producing cells in insulin-dependent T2D diabetic patients; the cells in this case could be evaluated for their ability to cure diabetes in the absence of needing to prevent both allogeneic and autoimmune responses.
SPINAL CORD INJURY
Is there any news on clinical trials for spinal cord injury? Le Ly
Kevin McCormack: The clinical trial CIRM was funding, with Asterias (now part of a bigger company called Lineage Cell Therapeutics, is now completed and the results were quite encouraging. In a news release from November of 2019 Brian Culley, CEO of Lineage Cell Therapeutics, described the results this way.
“We remain extremely excited about the potential for OPC1 (the name of the therapy used) to provide enhanced motor recovery to patients with spinal cord injuries. We are not aware of any other investigative therapy for SCI (spinal cord injury) which has reported as encouraging clinical outcomes as OPC1, particularly with continued improvement beyond 1 year. Overall gains in motor function for the population assessed to date have continued, with Year 2 assessments measuring the same or higher than at Year 1. For example, 5 out of 6 Cohort 2 patients have recovered two or more motor levels on at least one side as of their Year 2 visit whereas 4 of 6 patients in this group had recovered two motor levels as of their Year 1 visit. To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence. Just as importantly, the overall safety of OPC1 has remained excellent and has been maintained 2 years following administration, as measured by MRI’s in patients who have had their Year 2 follow-up visits to date. We look forward to providing further updates on clinical data from SCiStar as patients continue to come in for their scheduled follow up visits.”
Lineage Cell Therapeutics plans to meet with the FDA in 2020 to discuss possible next steps for this therapy.
In the meantime the only other clinical trial I know that is still recruiting is one run by a company called Neuralstem. Here is a link to information about that trial on the www.clinicaltrials.gov website.
Now that the Brainstorm ALS trial is finished looking for new patients do you have any idea how it’s going and when can we expect to see results? Angela Harrison Johnson
Dr. Ingrid Caras: The treated patients have to be followed for a period of time to assess how the therapy is working and then the data will need to be analyzed. So we will not expect to see the results probably for another year or two.
Are there treatments for autism or fragile x using stem cells? Magda Sedarous
Dr. Kelly Shepard: Autism and disorders on the autism spectrum represent a collection of many different disorders that share some common features, yet have different causes and manifestations, much of which we still do not understand. Knowing the origin of a disorder and how it affects cells and systems is the first step to developing new therapies. CIRM held a workshop on Autism in 2009 to brainstorm potential ways that stem cell research could have an impact. A major recommendation was to exploit stem cells and new technological advances to create cells and tissues, such as neurons, in the lab from autistic individuals that could then be studied in great detail. CIRM followed this recommendation and funded several early-stage awards to investigate the basis of autism, including Rett Syndrome, Fragile X, Timothy Syndrome, and other spectrum disorders. While these newer investigations have not yet led to therapies that can be tested in humans, this remains an active area of investigation. Outside of CIRM funding, we are aware of more mature studies exploring the effects of umbilical cord blood or other specific stem cell types in treating autism, such as an ongoing clinical trial conducted at Duke University.
What is happening with Parkinson’s research? Hanifa Gaphoor
Dr. Kent Fitzgerald: Parkinson’s disease certainly has a significant amount of ongoing work in the regenerative medicine and stem cell research.
The nature of cell loss in the brain, specifically the dopaminergic cells responsible for regulating the movement, has long been considered a good candidate for cell replacement therapy.
This is largely due to the hypothesis that restoring function to these cells would reverse Parkinson’s symptoms. This makes a lot of sense as front line therapy for the disease for many years has been dopamine replacement through L-dopa pills etc. Unfortunately, over time replacing dopamine through a pill loses its benefit, whereas replacing or fixing the cells themselves should be a more permanent fix.
Because a specific population of cells in one part of the brain are lost in the disease, multiple labs and clinicians have sought to replace or augment these cells by transplantation of “new” functional cells able to restore function to the area an theoretically restore voluntary motor control to patients with Parkinson’s disease.
Early clinical research showed some promise, however also yielded mixed results, using fetal tissue transplanted into the brains of Parkinson’s patients. As it turns out, the cell types required to restore movement and avoid side effects are somewhat nuanced. The field has moved away from fetal tissue and is currently pursuing the use of multiple stem cell types that are driven to what is believed to be the correct subtype of cell to repopulate the lost cells in the patient.
One project CIRM sponsored in this area with Jeanne Loring sought to develop a cell replacement therapy using stem cells from the patients themselves that have been reprogrammed into the kinds of cell damaged by Parkinson’s. This type of approach may ultimately avoid issues with the cells avoiding rejection by the immune system as can be seen with other types of transplants (i.e. liver, kidney, heart etc).
Still, others are using cutting edge gene therapy technology, like the clinical phase project CIRM is sponsoring with Krystof Bankiewicz to investigate the delivery of a gene (GDNF) to the brain that may help to restore the activity of neurons in the Parkinson’s brain that are no longer working as they should.
The bulk of the work in the field of PD at the present remains centered on replacing or restoring the dopamine producing population of cells in the brain that are affected in disease.
Any plans for Huntington’s?Nikhat Kuchiki
Dr. Lisa Kadyk: The good news is that there are now several new therapeutic approaches to Huntington’s Disease that are at various stages of preclinical and clinical development, including some that are CIRM funded. One CIRM-funded program led by Dr. Leslie Thompson at UC Irvine is developing a cell-based therapeutic that consists of neural stem cells that have been manufactured from embryonic stem cells. When these cells are injected into the brain of a mouse that has a Huntington’s Disease mutation, the cells engraft and begin to differentiate into new neurons. Improvements are seen in the behavioral and electrophysiological deficits in these mutant mice, suggesting that similar improvements might be seen in people with the disease. Currently, CIRM is funding Dr. Thompson and her team to carry out rigorous safety studies in animals using these cells, in preparation for submitting an application to the FDA to test the therapy in human patients in a clinical trial.
There are other, non-cell-based therapies also being tested in clinical trials now, using anti-sense oligonucleotides (Ionis, Takeda) to lower the expression of the Huntington protein. Another HTT-lowering approach is similar – but uses miRNAs to lower HTT levels (UniQure,Voyager)
TRAUMATIC BRAIN INJURY (TBI)
My 2.5 year old son recently suffered a hypoxic brain injury resulting in motor and speech disabilities. There are several clinical trials underway for TBI in adults. My questions are:
Will the results be scalable to pediatric use and how long do you think it would take before it is available to children?
I’m wondering why the current trials have chosen to go the route of intracranial injections as opposed to something slightly less invasive like an intrathecal injection?
Is there a time window period in which stem cells should be administered by, after which the administration is deemed not effective?
Dr. Kelly Shepard: TBI and other injuries of the nervous system are characterized by a lot of inflammation at the time of injury, which is thought to interfere with the healing process- and thus some approaches are intended to be delivered after that inflammation subsides. However, we are aware of approaches that intend to deliver a therapy to a chronic injury, or one that has occurred previously. Thus, the answer to this question may depend on how the intended therapy is supposed to work. For example, is the idea to grow new neurons, or is it to promote the survival of neurons of other cells that were spared by the injury? Is the therapy intended to address a specific symptom, such as seizures? Is the therapy intended to “fill a gap” left behind after inflammation subsides, which might not restore all function but might ameliorate certain symptoms.? There is still a lot we don’t understand about the brain and the highly sophisticated network of connections that cannot be reversed by only replacing neurons, or only reducing inflammation, etc. However, if trials are well designed, they should yield useful information even if the therapy is not as effective as hoped, and this information will pave the way to newer approaches and our technology and understanding evolves.
We have had a doctor recommending administering just the growth factors derived from MSC stem cells. Does the science work that way? Is it possible to isolate the growth factors and boost the endogenous growth factors by injecting allogenic growth factors?
Dr. Stephen Lin: Several groups have published studies on the therapeutic effects in non-human animal models of using nutrient media from MSC cultures that contain secreted factors, or extracellular vesicles from cells called exosomes that carry protein or nucleic acid factors. Scientifically it is possible to isolate the factors that are responsible for the therapeutic effect, although to date no specific factor or combination of factors have been identified to mimic the effects of the undefined mixtures in the media and exosomes. At present no regulatory approved clinical therapy has been developed using this approach.
PREDATORY STEM CELL CLINICS
What practical measures are being taken to address unethical practitioners whose bad surgeries are giving stem cell advances a bad reputation and are making forward research difficult?Kathy Jean Schultz
Dr. Geoff Lomax: Terrific question! I have been doing quite a bit research into the history of this issue of unethical practitioners and I found an 1842 reference to “quack medicines.” Clearly this is nothing new. In that day, the author appealed to make society “acquainted with the facts.”
In California, we have taken steps to (1) acquaint patients with the facts about stem cell treatments and (2) advance FDA authorized treatments for unmet medical needs.
First, CIRM work with Senator Hernandez in 2017 to write a law the requires provides to disclose to patient that a stem cell therapy has not been approved by the Food and Drug administration.
We continue to work with the State Legislature and Medical Board of California to build on policies that require accurate disclosure of the facts to patients.
Second, our clinical trial network the — Alpha Stem Cell Clinics – have supported over 100 FDA-authorized clinical trials to advance responsible clinical research for unmet medical needs.
I’m curious if adipose stem cell being used at clinics at various places in the country is helpful or beneficial?Cheri Hicks
Adipose tissue has been widely used particularly in plastic and reconstructive surgery. Many practitioners suggest adipose cells are beneficial in this context. With regard to regenerative medicine and / or the ability to treat disease and injury, I am not aware of any large randomized clinical trials that demonstrate the safety and efficacy of adipose-derived stem cells used in accordance with FDA guidelines.
I went to a “Luncheon about Stem Cell Injections”. It sounded promising. I went thru with it and got the injections because I was desperate from my knee pain. The price of stem cell injections was $3500 per knee injection. All went well. I have had no complications, but haven’t noticed any real major improvement, and here I am a year later. My questions are:
1) I wonder on where the typical injection cells are coming from?
2) I wonder what is the actual cost of the cells?
3) What kind of results are people getting from all these “pop up” clinics or established clinics that are adding this to there list of offerings?
Dr. Geoff Lomax: You raise a number of questions and point here; they are all very good and it’s is hard to give a comprehensive response to each one, but here is my reaction:
There are many practitioners in the field of orthopedics who sincerely believe in the potential of cell-based treatments to treat injury / pain
Most of the evidence presented is case reports that individuals have benefited
The challenge we face is not know the exact type of injury and cell treatments used.
Well controlled clinical trials would really help us understand for what cells (or cell products) and for what injury would be helpful
Prices of $3000 to $5000 are not uncommon, and like other forms of private medicine there is often a considerable mark-up in relation to cost of goods.
You are correct that there have not been reports of serious injury for knee injections
However the effectiveness is not clear while simultaneously millions of people have been aided by knee replacements.
Do stem cells have benefits for patients going through chemotherapy and radiation therapy?Ruperto
Dr. Kelly Shepard: The idea that a stem cell therapy could help address effects of chemotherapy or radiation is being and has been pursued by several investigators over the years, including some with CIRM support. Towards the earlier stages, people are looking at the ability of different stem cell-derived neural cell preparations to replace or restore function of certain brain cells that are damaged by the effects of chemotherapy or radiation. In a completely different type of approach, a group at City of Hope is exploring whether a bone marrow transplant with specially modified stem cells can provide a protective effect against the chemotherapy that is used to treat a form of brain cancer, glioblastoma. This study is in the final stage of development that, if all goes well, culminates with application to the FDA to allow initiation of a clinical trial to test in people.
Dr. Ingrid Caras: That’s an interesting and valid question. There is a Phase 1 trial ongoing that is evaluating a novel type of stem/progenitor cell from the umbilical cord of healthy deliveries. In animal studies, these cells have been shown to reduce the toxic effects of chemotherapy and radiation and to speed up recovery. These cells are now being tested in a First-in-human clinical trial in patients who are undergoing high-dose chemotherapy to treat their disease.
There is a researcher at Stanford, Michelle Monje, who is investigating that the role of damage to stem cells in the cognitive problems that sometimes arise after chemo- and radiation therapy (“chemobrain”). It appears that damage to stem cells in the brain, especially those responsible for producing oligodendrocytes, contributes to chemobrain. In CIRM-funded work, Dr. Monje has identified small molecules that may help prevent or ameliorate the symptoms of chemobrain.
Is it possible to use a technique developed to fight one disease to also fight another? For instance, the bubble baby disease, which has cured (I think) more than 50 children, may also help fight sickle cell anemia? Don Reed.
Dr. Lisa Kadyk: Hi Don. Yes, the same general technique can often be applied to more than one disease, although it needs to be “customized” for each disease. In the example you cite, the technique is an “autologous gene-modified bone marrow transplant” – meaning the cells come from the patient themselves. This technique is relevant for single gene mutations that cause diseases of the blood (hematopoietic) system. For example, in the case of “bubble baby” diseases, a single mutation can cause failure of immune cell development, leaving the child unable to fight infections, hence the need to have them live in a sterile “bubble”. To cure that disease, blood stem cells, which normally reside in the bone marrow, are collected from the patient and then a normal version of the defective gene is introduced into the cells, where it is incorporated into the chromosomes. Then, the corrected stem cells are transplanted back into the patient’s body, where they can repopulate the blood system with cells expressing the normal copy of the gene, thus curing the disease.
A similar approach could be used to treat sickle cell disease, since it is also caused by a single gene mutation in a gene (beta hemoglobin) that is expressed in blood cells. The same technique would be used as I described for bubble baby disease but would differ in the gene that is introduced into the patient’s blood stem cells.
Is there any concern that CIRM’s lack of support in basic research will hamper the amount of new approaches that can reach clinical stages? Jason
Dr. Kelly Shepard: CIRM always has and continues to believe that basic research is vital to the field of regenerative medicine. Over the past 10 years CIRM has invested $904 million in “discovery stage/basic research”, and about $215 million in training grants that supported graduate students, post docs, clinical fellows, undergraduate, masters and high school students performing basic stem cell research. In the past couple of years, with only a limited amount of funds remaining, CIRM made a decision to invest most of the remaining funds into later stage projects, to support them through the difficult transition from bench to bedside. However, even now, CIRM continues to sponsor some basic research through its Bridges and SPARK Training Grant programs, where undergraduate, masters and even high school students are conducting stem cell research in world class stem cell laboratories, many of which are the same laboratories that were supported through CIRM basic research grants over the past 10 years. While basic stem cell research continues to receive a substantial level of support from the NIH ($1.8 billion in 2018, comprehensively on stem cell projects) and other funders, CIRM believes continued support for basic research, especially in key areas of stem cell research and vital opportunities, will always be important for discovering and developing new treatments.
What is the future of the use of crispr cas9 in clinical trials in california/globally. Art Venegas
Dr. Kelly Shepard: CRISPR/Cas9 is a powerful gene editing tool. In only a few years, CRISPR/Cas9 technology has taken the field by storm and there are already a few CRISPR/Cas9 based treatments being tested in clinical trials in the US. There are also several new treatments that are at the IND enabling stage of development, which is the final testing stage required by the FDA before a clinical trial can begin. Most of these clinical trials involving CRISPR go through an “ex vivo” approach, taking cells from the patient with a disease causing gene, correcting the gene in the laboratory using CRISPR, and reintroducing the cells carrying the corrected gene back into the patient for treatment. Sickle cell disease is a prime example of a therapy being developed using this strategy and CIRM funds two projects that are preparing for clinical trials with this approach. CRISPR is also being used to develop the next generation of cancer T-cell therapies (e.g. CAR-T), where T-cells – a vital part of our immune system – are modified to target and destroy cancer cell populations. Using CRISPR to edit cells directly in patients “in vivo” (inside the body) is far less common currently but is also being developed. It is important to note that any FDA sanctioned “in vivo” CRISPR clinical trial in people will only modify organ-specific cells where the benefits cannot be passed on to subsequent generations. There is a ban on funding for what are called germ line cells, where any changes could be passed down to future generations.
CIRM is currently supporting multiple CRISPR/Cas9 gene editing projects in California from the discovery or most basic stage of research, through the later stages before applying to test the technique in people in a clinical trial.
While the field is new – if early safety signals from the pioneering trials are good, we might expect a number of new CRISPR-based approaches to enter clinical testing over the next few years. The first of these will will likely be in the areas of bone marrow transplant to correct certain blood/immune or metabolic diseases, and cancer immunotherapies, as these types of approaches are the best studied and furthest along in the pipeline.
Explain the differences between gene therapy and stem cell therapy?Renee Konkol
Dr. Stephen Lin: Gene therapy is the direct modification of cells in a patient to treat a disease. Most gene therapies use modified, harmless viruses to deliver the gene into the patient. Gene therapy has recently seen many success in the clinic, with the first FDA approved therapy for a gene induced form of blindness in 2017 and other approvals for genetic forms of smooth muscle atrophy and amyloidosis.
Stem cell therapy is the introduction of stem cells into patients to treat a disease, usually with the purpose of replacing damaged or defective cells that contribute to the disease. Stem cell therapies can be derived from pluripotent cells that have the potential to turn into any cell in the body and are directed towards a specific organ lineage for the therapy. Stem cell therapies can also be derived from other cells, called progenitors, that have the ability to turn into a limited number of other cells in the body. for example hematopoietic or blood stem cells (HSCs), which are found in bone marrow, can turn into other cells of the blood system including B-cells and T-cells: while mesenchymal stem cells (MSCs), which are usually found in fat tissue, can turn into bone, cartilage, and fat cells. The source of these cells can be from the patient’s own body (autologous) or from another person (allogeneic).
Gene therapy is often used in combination with cell therapies when cells are taken from the patient and, in the lab, modified genetically to correct the mutation or to insert a correct form of the defective gene, before being returned to patients. Often referred to as “ex vivo gene therapy” – because the changes are made outside the patient’s body – these therapies include Chimeric Antigen Receptor T (CAR-T) cells for cancer therapy and gene modified HSCs to treat blood disorders such as severe combined immunodeficiency and sickle cell disease. This is an exciting area that has significantly improved and even cured many people already.
Currently, how can the outcome of CIRM stem cell medicine projects and clinical trials be soundly interpreted when their stem cell-specific doses are not known?James L. Sherley, M.D., Ph.D., Director. Asymmetrex, LLC
Dr. Stephen Lin: Stem cell therapies that receive approval to conduct clinical trials must submit a package of data to the FDA that includes studies that demonstrate their effectiveness, usually in animal models of the disease that the cell therapy is targeting. Those studies have data on the dose of the cell therapy that creates the therapeutic effect, which is used to estimate cell doses for the clinical trial. CIRM funds discovery and translational stage awards to conduct these types of studies to prepare cell therapies for clinical trials. The clinical trial is also often designed to test multiple doses of the cell therapy to determine the one that has the best therapeutic effect. Dosing can be very challenging with cell therapies because of issues including survival, engraftment, and immune rejection, but CIRM supports studies designed to provide data to give the best estimate possible.
Is there any research on using stem cells to increase the length of long bones in people?” For example, injecting stem cells into the growth plates to see if the cells can be used to lengthen limbs.Sajid
Dr. Kelly Shepard: There is quite a lot of ongoing research seeking ways to repair bones with stem cell based approaches, which is not the same but somewhat related. Much of this is geared towards repairing the types of bone injuries that do not heal well naturally on their own (large gaps, dead bone lesions, degenerative bone conditions). Also, a lot of this research involves engineering bone tissues in the lab and introducing the engineered tissue into a bone lesion that need be repaired. What occurs naturally at the growth plate is a complex interaction between many different cell types, much of which we do not fully understand. We do not fully understand how to use the cells that are used to engineer bone tissue in the lab. However, a group at Stanford, with some CIRM support, recently discovered a “skeletal stem cell” that exists naturally at the ends of human bones and at sites of fracture. These are quite different than MSCs and offer a new path to be explored for repairing and generating bone.
What procedures are in place to ensure the quality and safety of stem cell treatments? How can patients guard against deceptive promotional practices for treatments that have no basis in science? What new procedures are needed to support patients and the development of new treatments?
These questions and others were discussed this past Wednesday by the Medical Board of California’s Stem Cell and Regenerative Therapy Task Force. The task force held an interested parties meeting to receive information and input on options to promote consumer protection.
Dr. Maria Millan started by providing the task force with an overview of the field in general and the 56 CIRM funded Clinical Trials to illustrate the enormous promise of the field. She then contrasted this promise against numerous reports of patients being harmed by unproven and unregulated stem cell treatments provided by practitioners operating outside their field of training. Dr. Millan emphasized the critical importance of having systems in place to provide assurance to patients that treatments are appropriate for their particular disease. She elaborated on CIRM’s core mantra that stem cell treatments be regulated, reputable and reliable. We discussed the three Rs in this posting. The fundamental aim is to put the patient interests at the center of a system that meets all regulatory and professional standards of care.
Dr. Mehrdad Abedi, Director of the UC Davis Alpha Stem Cell Clinic provided concrete examples of how they are implementing the 3Rs in their operations. Dr. Abedi emphasized the importance of best practices for manufacturing and processing stem cell products and for clinical care. He cited the operations at the UC Davis Institute for Regenerative Cures and the various oversight committees tasked with protecting the rights and interests of patients. Collectively, this approach, embraced by all the CIRM Alpha Stem Cell Clinics, serves to ensure all clinical trials regulated, reputable and reliable.
Dr. Charity Dean of the Department of Public Health described the role of the Food and Drug Branch in licensing facilities involved in the preparation, processing and labeling of drugs. This authority extends to facilities outside of California that ship products into the state. Dr. Dean illustrated how the Department of Public Health’s Food and Drug Branch licenses manufactures, and this licensing system is designed to protect patients using such products.
After discussion and public comment, the task force co-chair, Dr. Krauss suggested the Medical Board would consider options for patient protection, include:
Guidance and education materials for medical practitioners
Sample informed consent documents designed to inform patients about the potential risks and benefits of stem cell treatments