The briefing is a traditional kick-off event to mark JP Morgan week in the City, a time when hotel rooms go for $1,000 a night and just reserving a table in the lobby for meetings can set you back hundreds of dollars. Fortunately, the ARM briefing is free. And worth every penny.
Lambert ran down the numbers that highlighted how the field is growing and expanding:
987 companies world wide – most of those in the US
1,000 + clinical trials
$9.8 billion in revenue/investments
Saying “for many of these patients these therapies don’t just bring improvements, they bring dramatic improvements” Lambert pointed out that when those 1,000 clinical trials are fully enrolled it will mean 60,000 patients getting stem cell and gene therapies. She says it’s estimated that in the coming years around half a million patients in the US alone will get one of those therapies.
More and more of the clinical trials are at advanced stages:
100 Phase 3
591 Phase 2
381 Phase 1
The biggest sector for clinical trials is cancer, but there are also substantial numbers for central nervous system therapies, muscular skeletal and even rare diseases.
Lambert said there are two key issues facing the field in the coming year. One is improving the industry’s manufacturing capability to ensure we are able to produce the cells needed to treat large numbers of patients. As evidence she cited the fact that Pfizer and Novartis are investing hundreds of millions of dollars in in-house manufacturing facilities.
The second key issue is reimbursement, so that companies can get paid for delivering those treatments to patients. “There is appetite and interest in this from people around the world, but right now most conversations about reimbursement are taking place one at a time. We haven’t yet evolved to the point where we have standard models to help get products to market and help them be commercially successful.”
The forecast for the year ahead? “Sunny with some clouds. 2019 was a year of significant growth and we enter 2020 with hopes of continued expansion, as we look to grow the impact on patients.”
By Kelly Shepard, PhD., CIRM’s Associate Director, Discovery & Translation
CIRM has previously blogged about advances in treating certain forms of “bubble baby” disease”, where a person is born with a defect in their blood forming stem cells that results in a deficient immune system, rendering them vulnerable to lethal infections by all manner of bacteria, virus or germ.
If a suitable donor can be found, or if the patient’s own defective cells can be corrected through gene therapy approaches, it is now possible to treat or cure such disorders through a bone marrow transplant. In this procedure, healthy blood stem cells are infused into the patient, taking up residence in his or her bone marrow and dividing to give rise to functioning immune cells such as T cells and B cells.
Unfortunately, there is another type of “bubble baby” disease that cannot be treated by providing healthy blood stem cells, because the defective immune system is caused by a different culprit altogether- a missing or dysfunctional thymus.
T Cells Go to School
What is a thymus? Most of us give little thought to this leaf-shaped organ, which is large and important in our early childhoods, but becomes small and inconspicuous as we age. This transformation belies the critical role a thymus plays in the development of our adaptive immune systems, which takes place in our youth: to prepare our bodies to fight infections for the rest of our lives.
One might think of the thymus as a “school”, where immature T cells go to “learn” how to recognize and attack foreign antigens (surface markers), such as those found on microorganisms or tissues from other individuals. The thymus also “teaches” our immune system to distinguish “self” from “other” by eliminating any T cells that attack our own tissues. Without this critical function, our immune system could inadvertently turn against us, causing serious autoimmune disorders such as ulcerative colitis and myasthenia gravis.
Many children with a severely deficient or absent thymus, referred to as athymia, have inherited a chromosome that is missing a key stretch of genes on a region called 22q11. Doctors believe perhaps 1/2000-1/4000 babies are born with some type of deletion in this region, which leads to a variable spectrum of disorders called 22q11 syndrome that can affect just about any part of the body, and can even cause learning disabilities and mental illness.
Individuals with one form of 22q11, called DiGeorge Syndrome, are particularly affected in the heart, thymus, and parathyroid glands. In the United States, about 20 infants are born per year with the “complete” and most severe form of DiGeorge Syndrome, who lack a thymus altogether, and have severely depressed numbers of T cells for fighting infections. Without medical intervention, this condition is usually fatal by 24 months of age.
Optimism and Setback
Although there are no therapies approved by the Food and Drug Administration (FDA) for pediatric athymia, Dr. Mary Louise Markert at Duke University and Enzyvant, Inc. have been pioneering an experimental approach to treat children with complete DiGeorge syndrome.
In this procedure, discarded thymic tissues are collected from infants undergoing cardiac surgery, where some of the thymus needs to be removed in order for the surgeon to gain access to the heart. These tissues are processed to remove potentially harmful donor T cells and then transplanted into the thigh of an athymic DiGeorge patient.
Results from early clinical trials seemed promising, with more than 70% of patients surviving, including several who are now ten years post-transplant. Based on those results, in June of 2019 Enzyvant applied to the FDA for a Biologics License Application (BLA), which is needed to be able to sell the therapy in the US. Unfortunately, only a few months later, Enzyvant announced that the FDA had declined to approve the BLA due to manufacturing concerns.
While it may be possible to address these issues in time, the need to step back to the drawing board was a devastating blow to the DiGeorge Community, who have waited decades for a promising treatment to emerge on the horizon.
Despite the setback, there is reason to hope. In early 2019, CIRM granted a “Quest” Award to team of investigators at Stanford University to develop a novel stem cell based approach for treating thymic deficiency. Co-led by Katja Weinacht, a pediatric hematologist/oncologist, and Vittorio Sebastiano, a stem cell expert and developmental biologist, the team’s strategy is to coax induced pluripotent stem cells (iPS) in the laboratory to differentiate into thymic tissue, which could then be transplanted into patients using the route pioneered by Duke and Enzyvant.
The beauty of this new approach is that pluripotent stem cells are essentially immortal in culture, providing an inexhaustible supply of fresh thymic cells for transplant, thereby allowing greater control over the quality and consistency of donor tissues. A second major advantage is the possibility of using pluripotent cells from the patient him/herself as the source, which should be perfectly immune-matched and alleviate the risk of rejection and autoimmunity that comes with use of donated tissues.
Sounds easy, so what are the challenges? As with many regenerative medicine approaches, the key is getting a pluripotent stem cell to differentiate into the right type of cells in the lab, which is a very different environment than what cells experience naturally when they develop in the context of an embryo and womb, where many cells are interacting and providing complex, instructive cues to one another. The precise factors and timing all need to be worked out and in most cases, this is done with an incomplete knowledge of human development.
A second challenge relates to using cells from DiGeorge patients to produce thymic tissue, which are missing several genes on their 22nd chromosome and will likely require sophisticated genetic engineering to restore this ability.
Fortunately, Drs. Weinacht and Sebastiano are up to the challenge, and have already made progress in differentiating human induced pluripotent stem cells (iPS) into thymic lineage intermediates that appear to be expressing the right proteins at the right time. They plan to combine these cells with engineered materials to create a three-dimensional (3D) tissue that more closely resembles an authentic organ, and which can be tested for functionality in athymic mice.
There is more work to be done, but these advances, along with continued technological improvements and renewed efforts from Enzyvant, could forge a path to the clinic and lead to a brighter future for patients suffering from congenital athymia and other forms of thymic dysfunction.
This year the most widely read blog was actually one we wrote back in 2018. It’s the transcript of a Facebook Live: “Ask the Stem Cell Team” event about strokes and stroke recovery. Because stroke is the third leading cause of death and disability in the US it’s probably no surprise this blog has lasting power. So many people are hoping that stem cells will help them recover from a stroke.
But of the blogs that we wrote and posted this year there’s a really interesting mix of topics.
The most read 2019 blog was about a potential breakthrough in the search for a treatment for type 1 diabetes (T1D). Two researchers at UC San Francisco, Dr. Matthias Hebrok and Dr. Gopika Nair developed a new method of replacing the insulin-producing cells in the pancreas that are destroyed by type 1 diabetes.
Dr. Hebrok described it as a big advance saying: “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”
It’s not too surprising a blog about type 1 diabetes was at the top. This condition affects around 1.25 million Americans, a huge audience for any potential breakthrough. However, the blog that was the second most read is the exact opposite. It is about a rare disease called cystinosis. How rare? Well, there are only around 500 children and young adults in the US, and just 2,000 worldwide diagnosed with this condition.
It might be rare but its impact is devastating. A genetic mutation means children with this condition lack the ability to clear an amino acid – cysteine – from their body. The buildup of cysteine leads to damage to the kidneys, eyes, liver, muscles, pancreas and brain.
UC San Diego researcher Dr. Stephanie Cherqui and her team are taking the patient’s own blood stem cells and, in the lab, genetically re-engineering them to correct the mutation, then returning the cells to the patient. It’s hoped this will create a new, healthy blood system free of the disease.
Dr. Cherqui says if it works, this could help not just people with cystinosis but a wide array of other disorders: “We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders.”
The third most read blog was about another rare disease, but one that has been getting a lot of media attention this past year. Sickle cell disease affects around 100,000 Americans, mostly African Americans. In November the Food and Drug Administration (FDA) approved Oxbryta, a new therapy that reduces the likelihood of blood cells becoming sickle shaped and clumping together – causing blockages in blood vessels.
But our blog focused on a stem cell approach that aims to cure the disease altogether. In many ways the researchers in this story are using a very similar approach to the one Dr. Cherqui is using for cystinosis. Genetically correcting the mutation that causes the problem, creating a new, healthy blood system free of the sickle shaped blood cells.
Two other blogs deserve honorable mentions here as well. The first is the story of James O’Brien who lost the sight in his right eye when he was 18 years old and now, 25 years later, has had it restored thanks to stem cells.
The fifth most popular blog of the year was another one about type 1 diabetes. This piece focused on the news that the CIRM Board had awarded more than $11 million to Dr. Peter Stock at UC San Francisco for a clinical trial for T1D. His approach is transplanting donor pancreatic islets and parathyroid glands into patients, hoping this will restore the person’s ability to create their own insulin and control the disease.
2019 was certainly a busy year for CIRM. We are hoping that 2020 will prove equally busy and give us many new advances to write about. You will find them all here, on The Stem Cellar.
As we get close to the end of the year there is no shortage of lists of the “best of the year” and even this year the “best of the decade”. But when it comes to podcasts it would be hard to think of a better one than “Bad Batch”. It’s part stem cell research, part medical mystery and altogether engrossing.
It’s the work of Laura Beil, an award-winning journalist who follows the trail of a stem cell therapy that was supposed to help patients but instead left them battling life-threatening infections. It highlights how some clinics are able to find loopholes in the law that allow them to offer unproven and unapproved therapies, and how those therapies can put people’s lives at risk.
We have written about the dangers of predatory stem cell clinics several times, but in “Bad Batch” you get to hear the voices of the people affected, and ultimately the people responsible. It’s great journalism and fascinating story telling. And it’s a reminder of the work that needs to be done to stop this ever happening again.
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.
There are a growing number of predatory clinics in California and around the US, offering unproven stem cell therapies. For patients seeking a legitimate therapy it can often be hard finding a reliable clinic, one offering treatments based on the rigorous science required in a clinical trial sanctioned by the US Food and Drug Administration (FDA). That’s one of the reasons why the California Institute for Regenerative Medicine (CIRM) created the CIRM Alpha Stem Cell Clinic Network and we are delighted the clinics have now been chosen as a Core program of the American Society of Hematology (ASH) Sickle Cell Disease (SCD) Collaborative Trials Network.
The Alpha Clinics are a network of top California medical centers that specialize in delivering stem cell clinical trials to patients. It consists of five leading medical centers throughout California: City of Hope, University of California (UC) San Diego, UC Irvine & UC Los Angeles, UC Davis and UC San Francisco.
The mission of the ASH Research Collaborative SCD Clinical Trials Network is to improve outcomes for individuals with Sickle Cell Disease by promoting innovation in therapy development and clinical trial research.
“The key to finding a cure for this crippling disease, and finding it quickly, is to work together”, says Maria T. Millan, MD, President & CEO of CIRM. “That’s why we are delighted to be chosen as a core program for the ASH Sickle Cell Disease Clinical Trials Network. This partnership means we can share data and information about best practices to help us improve the quality of the research being done and the clinical care we can offer patients. We already have 23 clinical stage therapies in cell and gene therapy, including two clinical trials targeting SCD, so we feel we have a lot to bring to the partnership in terms of experience and expertise.”
Sickle Cell disease is a life-threatening blood disorder that affects 100,000 people, mostly African Americans, in the US. It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells that can block blood vessels causing intense pain, recurrent hospitalization, multi-organ damage and strokes.
“We hear a lot about the moonshot for curing cancer, but a moonshot for curing sickle cell disease should also be possible. Sickle cell disease was the first genetic disease that was discovered, and wouldn’t it be great if it is also one of the first ones we can cure in everyone?”
It is hoped that creating this network of clinical trial sites across the US will better serve an historically under-served population.
Establishing links and educational materials across these sites can increase patient engagement and recruitment
Standardizing resources across the network can ensure efficiency and coordination
Improving the training of clinical research staff can promote patient safety and trust and increase research quality
The CIRM Alpha Clinics Network has a proven track record of creating a faster, more streamlined approach in running clinical trials. It has developed the tools and systems to simultaneously launch clinical trials at multiple sites; created model non-disclosure agreements to make it easier for clinical trial sponsors to sign up; created a system to enable one Institutional Review Board (IRB) to approve a trial to be carried out at multiple sites rather than requiring each site to have its own IRB approval; developed best practices to quickly share experience and expertise across the network; and set up a database of over 20 million Californians to improve patient recruitment.
An Executive Summary prepared for the Western States Sickle Cell Disease Clinical Trials Network said: “the ASCC provides a formidable clinical trial unit uniquely qualified to deliver the next generation of cell and gene therapy products for SCD.”
There are many players who have a key role in helping make a stem cell therapy work. The scientists who develop the therapy, the medical team who deliver it and funders like CIRM who provide the money to make this all happen. But vital as they are, in some therapies there is another, even more important group; the people who donate life-saving organs and tissues for transplant and research.
Organ and tissue donation saves lives, increases knowledge of
diseases, and allow for the development of novel medications to treat them.
When individuals or their families authorize donation for transplant or medical
research, they allow their loved ones to build a long-lasting legacy of hope
that could not be accomplished in any other way.
Four of CIRM’s clinical trials involve organ donations –
three kidney transplant programs (you can read about those here,
and one targeting type 1
Dr. Nikole Neidlinger, the Chief
Medical Officer with Donor Network West – the federally designated organ and tissue recovery organization for
Northern California and Nevada – says it is important to recognize the critical
contribution made in a time of grief and crisis by the families of deceased
“For many families who donate, a
loved one has died, and they are in shock. Even so, they are willing to say yes
to giving others a second chance at life and to help others to advance science.
Without them, none of this would be possible. It’s the ultimate act of generosity
The latest CIRM-funded clinical trial involving donated
tissue is with Dr.
Peter Stock and his team at UCSF. They are working on a treatment for type
1 diabetes (T1D), where the body’s immune system destroys its own pancreatic
beta cells. These cells are necessary to produce insulin, which regulates blood
sugar levels in the body.
In the past people have tried transplanting beta cells,
from donated pancreatic islets, into patients with type 1 diabetes to try and
reverse the course of the disease. However, this requires islets from multiple
donors and the shortage of organ and tissue donors makes this difficult to do.
Dr. Stock’s clinical trial at UCSF aims to address these
limitations. He is going to transplant both pancreatic islets and
parathyroid glands, from the same donor, into T1 patients. It’s hoped this
combination approach will increase beta cell survival, potentially boosting long-term
insulin production and removing the need for multiple donors. And because
the transplant is placed in the patient’s forearm, it makes it easier to
monitor the effectiveness and accessibility of the islet transplants. Of equal
importance, the development of this site will facilitate the transplantation of
stem cell derived beta cells, which are very close to clinical application.
“As a transplant surgeon, it is an absolute privilege to
be able to witness the life-saving organ transplants made possible by the
selfless generosity of the donor families. It is hard to imagine how families
have the will to think about helping others at a time of their greatest grief.
It is this willingness to help others that restores my faith in humanity”
Donor Network West plays a
vital role in this process. In 2018 alone, the organization recovered 702 donor
samples for research. Thanks to the generosity of the donors/donor families, the donor
network has been able to provide parathyroid and pancreas tissue essential to
make this clinical trial a success”
“One organ donor can save the lives of up to eight people
and a tissue donor can heal more than 75 others,” says
Dr. Neidlinger. “For families, the knowledge that they are
transforming someone’s life, and possibly preventing another family from
experiencing this same loss, can serve as a silver lining during their time of
Currently, there are over 113,000 people in the U.S. waiting for an organ transplant, of which 84 % are in need of kidneys. Sadly, 22 people die every day waiting for an organ transplant that does not come in time. The prospect of an effective treatment for type 1 diabetes means hope for thousands of people living with the chronic condition.
satisfying to see two projects you have supported for a long time do well. That’s
particularly true when the projects in question are targeting conditions that
have no other effective therapies.
This week we learned
that a clinical trial we funded to help people with spinal cord injuries
continues to show benefits. This trial holds a special place in our hearts
because it is an extension of the first clinical trial we ever funded.
Initially it was with Geron,
and was later taken up by Asterias
Biotherapeutics, which has seen been bought by Lineage Cell Therapeutics Inc.
The therapy involved transplanting oligodendrocyte progenitor cells (OPCs), which are derived from human embryonic stem cells, into people who suffered recent spinal cord injuries that left them paralyzed from the neck down. OPCs play an important role in supporting and protecting nerve cells in the central nervous system, the area damaged in a spinal cord injury. It’s hoped the cells will help restore some of the connections at the injury site, allowing patients to regain some movement and feeling.
In a news
release, Lineage said that its OPC
therapy continues to report positive results, “where the overall safety profile
of OPC1 has remained excellent with robust motor recovery in upper extremities
maintained through Year 2 patient follow-ups available to date.”
Two years in the
patients are all continuing to do well, and no serious unexpected side effects
have been seen. They also reported:
– Motor level improvements
Five of six Cohort 2 patients achieved
at least two motor levels of improvement over baseline on at least one side as
of their 24-month follow-up visit.
In addition, one Cohort 2 patient
achieved three motor levels of improvement on one side over baseline as of the
patient’s 24-month follow-up visit; improvement has been maintained through the
patient’s 36-month follow-up visit.
Brian M. Culley, CEO of Lineage Cell Therapeutics called the news “exciting”, saying “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.”
The other good news came from Orchard Therapeutics, a company we have
partnered with on a therapy for Severe Combined Immunodeficiency (SCID) also
known as “bubble baby diseases” (we have blogged about this a lot including
In a news
release Orchard announced that the European Medicines Agency (EMA) has granted an accelerated
assessment for their gene therapy for metachromatic leukodystrophy (MLD). This
is a rare and often fatal condition that results in the build-up of sulfatides
in the brain, liver, kidneys and other organs. Over time this makes it harder
and harder for the person to walk, talk, swallow or eat.
Anne Dupraz-Poiseau, chief regulatory
officer of Orchard Therapeutics, says this is testimony to the encouraging
early results of this therapy. “We look forward to working with the EMA to
ensure this potentially transformative new treatment, if approved, reaches
patients in the EU as quickly as possible, and continuing our efforts to expand
patient access outside the EU.”
The accelerated assessment potentially
provides a reduced review timeline from 210 to 150 days, meaning it could be
available to a wider group of patients sooner.
Last week the CIRM Board awarded $5.53 million to Dr. Rosa Bacchetta at Stanford to complete the work necessary to conduct a clinical trial for IPEX syndrome. This is a rare disease caused by mutations in the FOXP3 gene which leaves people with the condition vulnerable to immune system attacks on their organs and tissues. These attacks can be devastating, even fatal.
At the Board meeting Taylor Lookofsky, a young man with IPEX syndrome, talked about the impact the condition has had on his life. The transcript of his talk is below.
It’s a powerful reminder that syndromes like this, because they affect a small number of people, are often overlooked and have few resources devoted to finding new treatments and cures. After reading Taylor’s story you come to appreciate his courage and determination, and why the funding CIRM provides is so important in helping researchers like Dr. Bacchetta find therapies to help people like Taylor.
“Good morning, my name is Taylor Lookofsky and I would first like to thank Rosa, who is one of the many doctors in my life. Rosa presented me with this amazing opportunity to come and speak to you today about my life and the challenges living with IPEX.
I’d like to give you some background into my
health challenges I’ve faced my entire life. Now to give some context to my
years of struggle, I am 28 years old, not 10 years younger as some may have
My first diagnosis came at the age of 1 ½ years
old -type 1 diabetes.
Soon after being diagnosed with type 1 diabetes,
I had to have a feeding tube inserted in my abdomen as I was restricted from
eating almost all foods due to unknown food allergies. I was not allowed to
ingest ANY food until the age of 6 years old. When I was finally introduced to
food, any food ingested was tasteless and felt like sandpaper on my tongue
since I had to train myself to eat.
Around age 10, I would be faced with the
beginning of a never-ending battle with my dermatitis. I remember specific
details where my mother had taken me to a dermatologist to try and figure out
what was happening to my skin as it was red, blotchy, oozing. I remember
shivering so badly that my mom had to ask the doctor’s office to turn the air
At age 18 I had been formally diagnosed with
IPEX. I lost my hair and my skin started a battle that was more intense than
any previous episode. I remember taking showers and clumps of my hair would
fall out, and I would cry in the shower not knowing what was going on.
At age 20, I would go through the most horrific
episode with my skin to date. I was bed ridden, on pain meds and could not
sleep. I had gone to all of my doctors trying to figure out what had triggered
this event, and no doctor could figure out what was happening, leaving me
extremely frustrated, depressed and drained of all energy. I went to the burn
center as a last resort and was then treated like a burn patient. To care for
these wounds, I would bathe, take a sponge and physically scrape these wounds
to keep them infection free and as clean as possible. When I would exit the
bath, I felt like a dried-up sponge and my skin was so tight that any movement would
make my skin crack open and start bleeding. To add to this, I had to use
medicated wraps to help with the healing process.
In an ongoing attempt to treat my many symptoms, I took a series of medications that came with side effects. I have had at least 15 surgeries to remove squamous cells caused by one of the medications: In 2018, my colon perforated. As a result, I now have a colostomy bag.
The IPEX symptoms have affected me not just physically, but mentally as well. I had lost all my hair and growth has been permanently stunted, and I have not reached the point in puberty as my male counterparts. I would go day by day and see all my peers and be envious that they were tall, had beards and hair, had relationships, and the confidence that I was lacking and admittedly, still lack to this day at times.
I’ve felt hopeless because there have been so few treatment options and with the treatment currently available, I have tried hundreds of medications and creams, and have had my blood drawn countless times in hopes of finding a medication that works for me, or a cure for this insufferable disease. However, nothing. As a result, I have been battling depression singe age 20. There were days that went by where I thought “I just don’t want to be here if this is what life is going to be like.”
The funding needed for Dr. Rosa’s therapy would be life changing in the way of new treatment options and potentially lead to a cure for this horrific disease.
I am determined to see that there is so much more to life than what society is telling me. I’ve decided that I would not conform to societies rules, and instead, tell society how I am going to live my unique and authentic life with IPEX.
I appreciate your time and consideration to fund this important research.”
In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.
Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:
Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome
BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma
Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer
City of Hope
Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsy
$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).
X-HIM is a hereditary immune disorder
observed predominantly in males in which there are abnormal levels of different
types of antibodies in the body.
Antibodies are also known as Immunoglobulin (Ig) and they combat
infections by attaching to germs and other foreign substances, marking them for
destruction. In infants with X-HIM,
there are normal or high levels of antibody IgM but low levels of antibodies
IgG, IgA, and IgE. The low level of
these antibodies make it difficult to fight off infection, resulting in
frequent pneumonia, sinus infections, ear infections, and parasitic
infections. Additionally, these infants
have an increased risk of cancerous growths.
The gene therapy approach Dr. Kuo is
continuing to develop involves using CRISPR/Cas9 technology to modify human
blood stem cells with a functional version of the gene necessary for normal
levels of antibody production. The
ultimate goal would be to take a patient’s own blood stem cells, modify them
with the corrected gene, and reintroduce them back into the patient.
CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.
$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).
MM is a type of blood cancer that forms in
the plasma cell, a type of white blood cell that is found in the bone marrow. An estimated 32,110 people in the United
States will be diagnosed with MM in 2019 alone.
Several treatment options are available to patients with MM, but there
is no curative therapy.
The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells. These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.
Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.
$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.
Ovarian cancer affects approximately 22,000
women per year in the United States alone.
Most ovarian cancer patients eventually develop resistance to
chemotherapy, leading to cancer progression and death, highlighting the need
for treatment of recurring ovarian cancer.
The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells. Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed. The additional copies of the virus will then go on to target neighboring tumor cells. This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.
million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to
develop a treatment for epilepsy.
Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.
therapy that Dr. Nicholas is developing will derive interneurons from human
embryonic stem cells (hESCs). These newly derived interneurons would then be
delivered to the brain via injection whereby the new cells are able to help
regulate aberrant brain activity and potentially eliminate or significantly
reduce the occurrence of seizures.