Facebook Live: Ask the Stem Cell Team

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

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.

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STROKE

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

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.

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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. 

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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.

We are aware of a clinical trial targeting acute hemorrhagic stroke that is being run by the Mayo clinic in Jacksonville Florida.

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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:

  1. Visual loss from damage to the retina
  2. You could have a normal eye with damage to the area of the brain that controls the eye’s movement
  3. 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. 

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VISION

Is there any stem cell therapy for optical nerve damage? Deanna Rice

Dr. Ingrid Caras

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

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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.

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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.

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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.

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DIABETES

What advances have been made using stem cells for the treatment of Type 2 Diabetes? Mary Rizzo

Dr. Ross Okamura

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.

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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.

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ALS

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.

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AUTISM

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.

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PARKINSON’S DISEASE

What is happening with Parkinson’s research? Hanifa Gaphoor

Dr. Kent Fitzgerald

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.   

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HUNTINGTON’S DISEASE

Any plans for Huntington’s? Nikhat Kuchiki

Dr. Lisa Kadyk

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)

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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?
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  • 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.

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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

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. 

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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

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.

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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?

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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.

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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.

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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. 

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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.

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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.

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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.

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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.

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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. 

USC study shows how tumor cells in the bloodstream can target distant organs

Various types of cancer can become particularly aggressive and difficult to treat once they spread from their initial point of origin to other parts of the body. This unfortunate phenomenon, known as metastasis, can make treatment very challenging, decreasing the chance of survival for the patient.

In order to better understand this process, a CIRM supported study at USC looked at breast cancer cells circulating in the blood that eventually invade the brain. The findings, which appear in Cancer Discovery, shed light on how tumor cells in the blood are able to target a particular organ, which may enable the development of treatments than can prevent metastasis from occurring.

Dr. Min Yu

Dr. Min Yu and her lab at USC were able to isolate breast cancer cells from the blood of breast cancer patients whose cancer had already metastasized. The team then expanded the number of cancer cells through a process known as cell culture. These expanded human tumor cells were then injected into the bloodstream of animal models. It was found that these cells migrated to the brain as was predicted.

Upon further analysis, Dr. Yu and her lab discovered a protein on the surface of the tumor cells in the bloodstream that enable them to breach the blood brain barrier, a protective layer around the brain that blocks the passage of certain substances, and enter the brain. Additionally, Dr. Yu and her team discovered another protein inside the tumor cells that shield them from the brain’s immune response, enabling these cells to grow inside the brain.

In a news release in Science Magazine, Dr. Yu talks about how these findings could be used to improve treatment and prevention options for those with aggressive cancers:

“We can imagine someday using the information carried by circulating tumor cells to improve the detection, monitoring and treatment of the spreading cancers. A future therapeutic goal is to develop drugs that get rid of circulating tumor cells or target those molecular signatures to prevent the spread of cancer.”

CIRM has also funded a separate clinical trial related to the treatment of breast cancer related brain metastases.

Predicting the Impact of Stem Cell Cures on Healthcare Burden in California

A new independent report says developing stem cell treatments and cures for some of the most common and deadly diseases could produce multi-billion dollar benefits for California in reduced healthcare costs and improved quality and quantity of life.

The report, by researchers at the University of Southern California’s Leonard D. Schaeffer Center for Health Policy & Economics, looked at the value of hypothetical future interventions to reduce or cure cancer, diabetes, stroke and blindness.

Predicting the future is always complicated and uncertain and many groups are looking at the best models to determine the value and economic impact of cell and gene therapy as the first products are just entering the market. This study provides some insights into the potential financial benefits of developing effective stem cell treatments for some of the most intractable diseases affecting California today.

The impact could affect millions of people. In 2018 for Californians over the age of 50:

  • Nearly half were predicted to develop diabetes in their lifetime
  • More than one third will experience a stroke
  • Between 5 and 8 percent will develop either breast, colorectal, lung, or prostate cancer

The report says that a therapy that decreased the incidence of diabetes by 50 percent in Californians over the age of 51 would translate into a gain for the state of $322 billion in social value between now and 2050. Even just reducing diabetes 10% would lead to a gain of $60 billion in social value over the same period.

  • For stroke a 50 percent reduction would generate an estimated $229 billion in social value. A 10 percent reduction would generate $47 billion
  • For breast cancer a 50 percent reduction would generate $56 billion in social value; for colorectal cancer it would be $72 billion; for lung cancer $151 billion; and prostate cancer $53 billion. 

The impact of a cure for any one of those diseases would be enormous. For example, a 51-year-old woman cured of lung cancer could expect to gain a lifetime social value of almost half a million dollars ($467,275). That’s a measure of years of healthy life gained, of years spent enjoying time with family and friends and not wasting away or lying in a hospital bed.

The researchers say: “Though advances in scientific research defy easy predictions, investing in biomedical research is important if we want to reduce the burden of common and costly diseases for individuals, their families, and society. These findings show the value and impact breakthrough treatments could have for California.”

“Put in this context, the CIRM investment would be worthwhile if it increased our chances of success even modestly. Against the billions of dollars in disease burden facing California, the relatively small initial investment is already paying dividends as researchers work to bring new therapies to patients.”

The researchers determined the “social value” using a measure called a quality adjusted life-year (QALY). This is a way of estimating the cost effectiveness and consequences of treating or not treating a disease. For example, one QALY is equivalent to one year of perfect health for an individual. In this study the value of that year was estimated at $150,000. If someone is sick with, say, diabetes, their health would be estimated to be 0.5 QALY or $75,000. So, the better health a person enjoys and the longer they enjoy it the higher QALY score they accumulate. In the case of a disease affecting millions of people in that state or country that can obviously lead to very large QALY scores representing potentially billions of dollars.

New Report Says CIRM Produces Big Economic Boost for California

An independent Economic Impact Report says the California Institute for Regenerative Medicine (CIRM) has had a major impact on California’s economy, creating tens of thousands of new jobs, generating hundreds of millions of dollars in new taxes, and producing billions of dollars in additional revenue for the state.

The report, done by Dan Wei and Adam Rose at the Price School of Public Policy at the University of Southern California, looked at the impacts of CIRM funding on both the state and national economy from the start of the Stem Cell Agency in 2004 to the end of 2018.

The total impacts on the California economy are estimated to be:

  • $10.7 billion of additional gross output (sales revenue)
  • $641.3 million of additional state/local tax revenues
  • $726.6 million of additional federal tax revenues
  • 56,549 additional full-time equivalent (FTE) jobs, half of which offer salaries considerably higher than the state average

Maria Millan, M.D., CIRM’s President and CEO, says the report reflects the Agency’s role in building an ecosystem to accelerate the translation of important stem cell science to solutions for patients with unmet medical needs. “CIRM’s mission on behalf of patients has been the priority from day one, but this report shows that CIRM funding brings additional benefits to the state. This report reflects how CIRM is promoting economic growth in California by attracting scientific talent and additional capital, and by creating an environment that supports the development of businesses and commercial enterprises in the state”

In addition to the benefits to California, the impacts outside of California on the US economy are estimated to be:

  • $4.7 billion of additional gross output (sales revenue)
  • $198.7 million of additional state (non-Californian) & local tax revenue
  • $208.6 million of additional federal tax revenues
  • 25,816 additional full-time equivalent (FTE) jobs

The researchers summarize their findings, saying: “In terms of economic impacts, the state’s investment in CIRM has paid handsome dividends in terms of output, employment, and tax revenues for California.”

The estimates in the report are based on the economic stimulus created by CIRM funding and by the co-funding that researchers and companies were required to provide for clinical and late-stage preclinical projects. The estimates also include:

  • Investments in CIRM-supported projects from private funders such as equity investments, public offerings and mergers and acquisitions,
  • Follow-on funding from the National Institutes of Health and other organizations due to data generated in CIRM-funded projects
  • Funding generated by clinical trials held at CIRM’s Alpha Stem Cell Clinics network

The researchers state “Nearly half of these impacts emanate from the $2.67 billion CIRM grants themselves.”

“The economic impact of California’s investment in stem and regenerative cell research is reflective of significant progress in this field that was just being born at the time of CIRM’s creation,” says Dr. Millan. “We fund the most promising projects based on rigorous science from basic research into clinical trials. We partnered with researchers and companies to increase the likelihood of success and created specialized infrastructure such as the Alpha Clinics Network to support the highest quality of clinical care and research standards for these novel approaches.  The ecosystem created by CIRM has attracted scientists, companies and capital from outside the state to California. By supporting promising science projects early on, long before most investors were ready to come aboard, we enabled our scientists to make progress that positioned them to attract significant commercial investments into their programs and into California.”

These partnerships have helped move promising therapies out of the lab and into clinical trials for companies like Orchard Therapeutics’ successful treatment for Severe Combined Immunodeficiency and Forty Seven Inc.’s innovative approach to treating cancer.

Dr. Don Kohn: Photo courtesy UCLA Jonsson Comprehensive Cancer Center

“I think one of the greatest strengths of CIRM has been their focus on development of new stem cell therapies that can become real medicines,” says UCLA and Orchard Therapeutics’ Don Kohn, M.D. “This has meant guiding academic investigators to do the things that may be second nature in industry/pharmaceutical companies but are not standard for basic or clinical research.  The support from CIRM to perform the studies and regulatory activities needed to navigate therapies through the FDA and to form alliances with biotech and pharma companies has allowed the stem cell gene therapy we developed to treat SCID babies to be advanced and licensed to Orchard Therapeutics who can make it available to patients across the country.”

Dr. Mark Chao: Photo courtesy Forty Seven Inc.

“CIRM’s support has been instrumental to our early successes and our ability to rapidly progress Forty Seven’s CD47 antibody targeting approach with magrolimab,” says Mark Chao, M.D., Ph.D., Founder and Vice President of Clinical Development at Forty Seven Inc. “ CIRM was an early collaborator in our clinical programs, and will continue to be a valued partner as we move forward with our MDS/AML clinical trials.”

The researchers say the money generated by partnerships and investments, what is called “deal-flow funding”, is still growing and that the economic benefits created by them are likely to continue for some time: “Deal-flow funding usually involves several waves or rounds of capital infusion over many years, and thus is it expected that CIRM’s past and current funding will attract increasing amounts of industry investment and lead to additional spending injections into the California economy in the years to come.”

They conclude their report by saying: “CIRM has led to California stem cell research and development activities becoming a leader among the states.”

Scientists at USC untangle the mysteries of cellular reprogramming- a method that could be used to treat diseases

Dr. Justin Ichida, Assistant Professor at USC and lead author of the study

Scientists have long tried to repurpose cells in order to potentially treat various types of conditions. This process, called reprogramming, involves changing one type of cell into another, such as a blood cell into a muscle cell or nerve cell. Although the technique has been around for decades, it has only been effective 1% of the time.

Fortunately, thanks in part to a CIRM grant, Dr. Justin Ichida and other researchers at USC have been able to untangle this complicated process to ensure reprogramming happens more efficiently. The researchers were able to figure out a process that reprograms cells much more reliably than previous methods.

USC scientists have found a solution to untangle twisty DNA, removing kinks so the molecules can be used to reprogram cells to advance regenerative medicine to treat disease.
Photo courtesy of Illustration/iStock

The technique the scientists developed uses an enzyme to untangle reprogramming DNA, similar to how a hairdresser conditions untangled hair. Since DNA molecules are twisty by nature, due to the double helix configuration, they do not respond well when manipulated to change itself. Therefore, reprogramming DNA requires uncoiling, yet when scientists begin to unravel the molecules, they knot up tighter.

“Think of it as a phone cord, which is coily to begin with, then gets more coils and knots when something is trying to harm it,” Dr. Ichida said in a press release by USC.

To smooth the kinks, the researchers treated cells with a chemical and genetic cocktail that activates enzymes that open up the DNA molecules. This process releases the coiled tension and lays out the DNA smoothly, leading to more efficient cellular reprogramming.

This new technique works almost 100% of the time and has been proven in human and mouse cells. The increased efficiency of this techniques opens the possibilities for studying disease development and drug treatments. New cells could be created to replace lost cells or acquire cells that can’t be extracted from people, a problem observed in Parkinson’s, ALS, and other neurological diseases.

Moreover, since these reprogrammed cells are the same age as the parent cell, they could be used to better understand age-related diseases. It is possible that the reprogrammed cells may be better at creating age-accurate models of human disease, which are useful to study a wide array of degenerative diseases and accelerated aging syndromes.

To summarize his work, Dr. Ichida states in the USC press release that,

“A modern approach for disease studies and regenerative medicine is to induce cells to switch their identity. This is called reprogramming, and it enables the attainment of inaccessible tissue types from diseased patients for examination, as well as the potential restoration of lost tissue. However, reprogramming is extremely inefficient, limiting its utility. In this study, we’ve identified the roadblock that prevents cells from switching their identity. It turns out to be tangles on the DNA within cells that form during the reprogramming process. By activating enzymes that untangle the DNA, we enable near 100% reprogramming efficiency.”

The full findings of this study can be found in Cell Stem Cell.

CIRM Board Approves $19.7 Million in Awards for Translational Research Program

In addition to approving funding for breast cancer related brain metastases last week, the CIRM Board also approved an additional $19.7 million geared towards our 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 getting into the details of each project, here is a table with a brief synopsis of the awards:

TRAN1 – 11532

Illustration of a healthy eye vs eye with AMD

$3.73 million was awarded to Dr. Mark Humayun at USC to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD).

AMD is an eye disease that causes severe vision impairment, resulting in the inability to read, drive, recognize faces, and blindness if left untreated.  It is the leading cause of vision loss in the U.S. and currently affects over 2 million Americans.  By the year 2050, it is projected that the number of affected individuals will more than double to over 5 million.  A layer of cells in the back of the eye called the retinal pigment epithelium (RPE) provide support to photoreceptors (PRs), specialized cells that play an important role in our ability to process images.  The dysfunction and/or loss of RPE cells plays a critical role in the loss of PRs and hence the vision problems observed in AMD.  One form of AMD is known as dry AMD (dAMD) and accounts for about 90% of all AMD cases.

The approach that Dr. Humayun is developing will use a biologic product produced by human embryonic stem cells (hESCs). This material will be injected into the eye of patients with early development of dAMD, supporting the survival of photoreceptors in the affected retina.

TRAN1 – 11579

Illustration depicting the role neuronal relays play in muscle sensation

$6.23 million was awarded to Dr. Mark Tuszynski at UCSD to develop a neural stem cell therapy for spinal cord injury (SCI).

According to data from the National Spinal Cord Injury Statistical Center, as of 2018, SCI affects an estimated 288,000 people in the United States alone, with about 17,700 new cases each year. There are currently no effective therapies for SCI. Many people suffer SCI in early adulthood, leading to life-long disability and suffering, extensive treatment needs and extremely high lifetime costs of health care.

The approach that Dr. Tuszynski is developing will use hESCs to create neural stem cells (NSCs).  These newly created NSCs would then be grafted at the site of injury of those with SCI.  In preclinical studies, the NSCs have been shown to support the formation of neuronal relays at the site of SCI.  The neuronal relays allow the sensory neurons in the brain to communicate with the motor neurons in the spinal cord to re-establish muscle control and movement.

TRAN1 – 11548

Graphic depicting the challenges of traumatic brain injury (TBI)

$4.83 million was awarded to Dr. Brian Cummings at UC Irvine to develop a neural stem cell therapy for traumatic brain injury (TBI).

TBI is caused by a bump, blow, or jolt to the head that disrupts the normal function of the brain, resulting in emotional, mental, movement, and memory problems. There are 1.7 million people in the United States experiencing a TBI that leads to hospitalization each year. Since there are no effective treatments, TBI is one of the most critical unmet medical needs based on the total number of those affected and on a cost basis.

The approach that Dr. Cummings is developing will also use hESCs to create NSCs.  These newly created NSCs would be integrated with injured tissue in patients and have the ability to turn into the three main cell types in the brain; neurons, astrocytes, and oligodendrocytes.  This would allow for TBI patients to potentially see improvements in issues related to memory, movement, and anxiety, increasing independence and lessening patient care needs.

TRAN1 – 11628

Illustration depicting the brain damage that occurs under hypoxic-ischemic conditions

$4.96 million was awarded to Dr. Evan Snyder at Sanford Burnham Prebys to develop a neural stem cell therapy for perinatal hypoxic-ischemic brain injury (HII).

HII occurs when there is a lack of oxygen flow to the brain.  A newborn infant’s body can compensate for brief periods of depleted oxygen, but if this lasts too long, brain tissue is destroyed, which can cause many issues such as developmental delay and motor impairment.  Current treatment for this condition is whole-body hypothermia (HT), which consists of significantly reducing body temperature to interrupt brain injury.  However, this is not very effective in severe cases of HII. 

The approach that Dr. Snyder is developing will use an established neural stem cell (NSC) line.   These NSCs would be injected and potentially used alongside HT treatment to increase protection from brain injury.

Regulated, reputable, and reliable – distinguishing legitimate clinical trials from predatory clinics

Here at CIRM, we get calls every day from patients asking us if there are any trials or therapies available to treat their illness or an illness affecting a loved one. Unfortunately, there are some predatory clinics that try to take advantage of this desperation by advertising unproven and unregulated treatments for a wide range of diseases such as Diabetes, Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS).

A recent article in the Los Angeles Times describes how one of these predatory stem cell clinics is in a class action lawsuit related to false advertising of 100% patient satisfaction. Patients were led to believe that this percentage was related to the effectiveness of the treatment, when in fact it had to do with satisfaction related to hospitality, hotel stay, and customer service. These kinds of deceptive tactics are commonplace for sham clinics and are used to convince people to pay tens of thousands of dollars for sham treatments.

But how can a patient or loved one distinguish a legitimate clinical trial or treatment from those being offered by predatory clinics? We have established the “fundamental three R’s” to help in making this distinction.

REGULATED

The United States Food and Drug Administration (FDA) has a regulated process that it uses in evaluating potential treatments from researchers seeking approval to test these in a clinical trial setting.  This includes extensive reviews by scientific peers in the community that are well informed on specific disease areas. Those that adhere to these regulations get an FDA seal of approval and are subject to extensive oversight to protect patients participating in this trial. Additionally, these regulations ensure that the potential treatments are properly evaluated for effectiveness. The 55 clinical trials that we have currently funded as well as the clinical trials being conducted in our Alpha Stem Cell Clinic Network all have this FDA seal of approval. In contrast to this, the treatments offered at predatory clinics have not gone through the rigorous standards necessary to obtain FDA approval.

REPUTABLE

We have partnered with reputable institutions to carry out the clinical trials we have funded and establish our Alpha Stem Cell Clinic Network. These are institutions that adhere to the highest scientific standards necessary to effectively evaluate potential treatments and communicate these results with extreme accuracy. These institutions have expert scientists, doctors, and nurses in the field and adhere to rigorous standards that have earned these institutions a positive reputation for carrying out their work.  The sites for the Alpha Stem Cell Clinic Network include City of Hope, UCSF, UC San Diego, UCLA, UC Davis, and UC Irvine.  In regards to the clinical trials we have directly funded, we have collaborated with other prestigious institutions such as Stanford and USC.  All these institutions have a reputation for being respected by established societies and other professionals in the field. The reputation that predatory clinics have garnered from patients, scientists, and established doctors has been a negative one. An article published in The New York Times has described the tactics used by these predatory clinics as unethical and their therapies have often been shown to be ineffective.

RELIABLE

The clinical trials we fund and those offered at our Alpha Stem Cell Clinic Network are reliable because they are trusted by patients, patient advocacy groups, and other experts in the field of regenerative medicine. A part of being reliable involves having extensive expertise and training to properly evaluate and administer treatments in a clinical trial setting. The doctors, nurses, and other experts involved in clinical trials given the go-ahead by the FDA have extensive training to carry out these trials.  These credentialed specialists are able to administer high quality clinical care to patients.  In a sharp contrast to this, an article published in Reuters showed that predatory clinics not only administer unapproved stem cell treatments to patients, but they use doctors that have not received training related to the services they provide.

Whenever you are looking at a potential clinical trial or treatment for yourself or a loved one, just remember the 3 R’s we have laid out in this blog.

Regulated, reputable, and reliable.

“A new awakening”: One patient advocate’s fight for her daughters life

We often talk about the important role that patient advocates play in helping advance research. That was demonstrated in a powerful way last week when the CIRM Board approved almost $12 million to fund a clinical trial targeting a rare childhood disorder called cystinosis.

The award, to Stephanie Cherqui and her team at UC San Diego (in collaboration with UCLA) was based on the scientific merits of the program. But without the help of the cystinosis patient advocate community that would never have happened. Years ago the community held a series of fundraisers, bake sales etc., and used the money to help Dr. Cherqui get her research started.

That money enabled Dr. Cherqui to get the data she needed to apply to CIRM for funding to do more detailed research, which led to her award last week. There to celebrate the moment was Nancy Stack. Her testimony to the Board was a moving celebration of how long they have worked to get to this moment, and how much hope this research is giving them.

Nancy Stack is pictured in spring 2018 with her daughter Natalie Stack and husband Geoffrey Stack. (Lar Wanberg/Cystinosis Research Foundation)

Hello my name is Nancy Stack and I am the founder and president of the Cystinosis Research Foundation.  Our daughter Natalie was diagnosed with cystinosis when she was an infant. 

Cystinosis is a rare disease that is characterized by the abnormal accumulation of cystine in every cell in the body.  The build-up of cystine eventually destroys every organ in the body including the kidneys, eyes, liver, muscles, thyroid and brain.  The average age of death from cystinosis and its complications is 28 years of age.

For our children and adults with cystinosis, there are no healthy days. They take between 8-12 medications around the clock every day just to stay alive – Natalie takes 45 pills a day.  It is a relentless and devastating disease.

Medical complications abound and our children’s lives are filled with a myriad of symptoms and treatments – there are g-tube feedings, kidney transplants, bone pain, daily vomiting,  swallowing difficulties, muscle wasting, severe gastrointestinal side effects and for some blindness.   

We started the Foundation in 2003.  We have worked with and funded Dr. Stephanie Cherqui since 2006.   As a foundation, our resources are limited but we were able to fund the initial grants for Stephanie’s  Stem Cell studies. When CIRM awarded a grant to Stephanie in 2016, it allowed her to complete the studies, file the IND and as a result, we now have FDA approval for the clinical trial. Your support has changed the course of this disease. 

When the FDA approved the clinical trial for cystinosis last year, our community was filled with a renewed sense of hope and optimism.  I heard from 32 adults with cystinosis – all of them interested in the clinical trial.  Our adults know that this is their only chance to live a full life. Without this treatment, they will die from cystinosis.  In every email I received, there was a message of hope and gratitude. 

I received an email from a young woman who said this, “It’s a new awakening to learn this morning that human clinical trials have been approved by the FDA. I reiterate my immense interest to participate in this trial as soon as possible because my quality of life is at a low ebb and the trial is really my only hope. Time is running out”. 

And a mom of a 19 year old young man who wants to be the first patient in the trial wrote and said this, “On the day the trial was announced I started to cry tears of pure happiness and I thought, a mother somewhere gets to wake up and have a child who will no longer have cystinosis. I felt so happy for whom ever that mom would be….I never imagined that the mom I was thinking about could be me. I am so humbled to have this opportunity for my son to try to live disease free.

My own daughter ran into my arms that day and we cried tears of joy – finally, the hope we had clung to was now a reality. We had come full circle.  I asked Natalie how it felt to know that she could be cured and she said, “I have spent my entire life thinking that I would die from cystinosis in my 30s but now, I might live a full life and I am thinking about how much that changes how I think about my future. I never planned too far ahead but now I can”. 

As a mother, words can’t possible convey what it feels like to know that my child has a chance to live a long, healthy life free of cystinosis – I can breathe again. On behalf of all the children and adults with cystinosis, thank you for funding Dr. Cherqui, for caring about our community, for valuing our children and for making this treatment a reality.  Our community is ready to start this trial – thank you for making this happen.

*************

CIRM will be celebrating the role of patient advocates at a free event in Los Angeles tomorrow. It’s at the LA Convention Center and here are the details. And did I mention it’s FREE!

Tue, June 25, 2019 – 6:00 PM – 7:00 PM PDT

Petree Hall C., Los Angeles Convention Center, 1201 South Figueroa Street Los Angeles, CA 90015

And on Wednesday, USC is holding an event highlighting the progress being made in fighting diseases that destroy vision. Here’s a link to information about the event.

Taking the message to the people: fighting for the future of stem cell research in California

Stem cells have been in the news a lot this week, and not necessarily for the right reason.

First, the US Food and Drug Administration (FDA) won a big legal decision in its fight to crack down on clinics offering bogus, unproven and unapproved stem cell therapies.

But then came news that another big name celebrity, in this case Star Trek star William Shatner, was going to one of these clinics for an infusion of what he called “restorative cells”.

It’s a reminder that for every step forward we take in trying to educate the public about the dangers of clinics offering unproven therapies, we often take another step back when a celebrity essentially endorses the idea.

So that’s why we are taking our message directly to the people, as often as we can and wherever we can.

In June we are going to be holding a free, public event in Los Angeles to coincide with the opening of the International Society for Stem Cell Research’s Annual Conference, the biggest event on the global stem cell calendar. There’s still time to register for that by the way. The event is from 6-7pm on Tuesday, June 25th in Petree Hall C., at the Los Angeles Convention Center at 1201 South Figueroa Street, LA 90015.

The event is open to everyone and it’s FREE. We have created an Eventbrite page where you can get all the details and RSVP if you are coming.

It’s going to be an opportunity to learn about the real progress being made in stem cell research, thanks in no small part to CIRM’s funding. We’re honored to be joined by UCLA’s Dr. Don Kohn, who has helped cure dozens of children born with a fatal immune system disorder called severe combined immunodeficiency, also known as “bubble baby disease”. And we’ll hear from the family of one of those children whose life he helped save.

And because CIRM is due to run out of money to fund new projects by the end of this year you’ll also learn about the very real concerns we have about the future of stem cell research in California and what can be done to address those concerns. It promises to be a fascinating evening.

But that’s not all. Our partners at USC will be holding another public event on stem cell research, on Wednesday June 26th from 6.30p to 8pm. This one is focused on treatments for age-related blindness. This features some of the top stem cell scientists in the field who are making encouraging progress in not just slowing down vision loss, but in some cases even reversing it.

You can find out more about that event here.

We know that we face some serious challenges in trying to educate people about the risks of going to a clinic offering unproven therapies. But we also know we have a great story to tell, one that shows how we are already changing lives and saving lives, and that with the support of the people of California we’ll do even more in the years to come.

Rats, research and the road to new therapies

Don Reed

Don Reed has been a champion of CIRM even before there was a CIRM. He’s a pioneer in pushing for funding for stem cell research and now he’s working hard to raise awareness about the difference that funding is making.

In a recent article on Daily Kos, Don highlighted one of the less celebrated partners in this research, the humble rat.

A BETTER RAT? Benefit #62 of the California Stem Cell Agency

By Don C. Reed

When I told my wife Gloria I was writing an article about rats, she had several comments, including: “Oo, ugh!” and also “That’s disgusting!”

Obviously, there are problems with rats, such as when they chew through electrical wires, which may cause a short circuit and burn down the house. Also, they are blamed for carrying diseased fleas in their ears and spreading the Black Plague, which in 1340 killed half of China and one-third of Europe—but this is not certain. The plague may in fact have been transmitted by human-carried parasites.

But there are positive aspects to rats as well. For instance: “…a rat paired with  another that has a disability…will be very kind to the other rat. Usually, help is offered with food, cleaning, and general care.”—GUIDE TO THE RAT, by Ginger Cardinal.

Above all, anyone who has ever been sick owes a debt to rats, specifically the Norway rat with that spectacular name, rattus norvegicus domesticus, found in labs around the world.

I first realized its importance on March 1, 2002, when I held in my hand a rat which had been paralyzed, but then recovered the use of its limbs.

The rat’s name was Fighter, and she had been given a derivative of embryonic stem cells, which restored function to her limbs. (This was the famous stem cell therapy begun by Hans Keirstead with a Roman Reed grant, developed by Geron, and later by CIRM and Asterias, which later benefited humans.)

As I felt the tiny muscles struggling to be free, it was like touching tomorrow— while my paralyzed son, Roman Reed, sat in his wheelchair just a few feet away.

Was it different working with rats instead of mice? I had heard that the far smaller lab mice were more “bitey” than rats.  

Wanting to know more about the possibilities of a “better rat”, I went to the CIRM website, (www.cirm.ca.gov) hunted up the “Tools and Technology III” section, and the following complicated sentence::

“Embryonic stem cell- based generation of rat models for assessing human cellular therapies.”

Hmm. With science writing, it always takes me a couple of readings to know what they were talking about. But I recognized some of the words, so that was a start.

“Stemcells… rat models… human therapies….”  

I called up Dr. Qilong Ying, Principle Investigator (PI) of the study.

As he began to talk, I felt a “click” of recognition, as if, like pieces of a puzzle, facts were fitting together.

It reminded me of Jacques Cousteau, the great underwater explorer, when he tried to invent a way to breathe underwater. He had the compressed air tank, and a mouthpiece that would release air—but it came in a rush, not normal breathing.

So he visited his friend, race car mechanic Emil Gagnan, and told him, “I need something that will give me air, but only when I inhale,”– and Gagnan said: “Like that?” and pointed to a metal contraption on a nearby table.

It was something invented for cars. But by adding it to what Cousteau already had, the Cousteau-Gagnan SCUBA (Self Contained Underwater Breathing Apparatus) gear was born—and the ocean could now be explored.

Qi-Long Ying’s contribution to science may also be a piece of the puzzle of cure…

A long-term collaboration with Dr. Austin Smith centered on an attempt to do with rats what had done with mice.

In 2007, the  Nobel Prize in Medicine had been won by Dr. Martin Evans, Mario Capecchi, and Oliver Smithies. Working independently, they developed “knock-out” and “knock-in” mice, meaning to take out a gene, or put one in.  

But could they do the same with rats?

 “We and others worked very, very hard, and got nowhere,” said Dr. Evans.

Why was this important?

Many human diseases cannot be mimicked in the mouse—but might be in the rat. This is for several reasons: the rat is about ten times larger; its internal workings are closer to those of a human; and the rat is considered several million years closer (in evolutionary terms) to humans than the mouse.

In 2008 (“in China, that is the year of the rat,” noted Dr. Ying in our conversation) he received the first of three grants from CIRM.

“We proposed to use the classical embryonic stem cell-based gene-targeting technology to generate rat models mimicking human heart failure, diabetes and neurodegenerative diseases…”

How did he do?

In 2010, Science Magazine honored him with inclusion in their “Top 10 Breakthroughs for using embryonic stem cell-based gene targeting to produce the world’s first knockout rats, modified to lack one or more genes…”

And in 2016, he and Dr. Smith received the McEwen Award for Innovation,  the highest honor bestowed by the International Society for Stem Cell Research (ISSCR).

Using knowledge learned from the new (and more relevant to humans) lab rat, it may be possible to develop methods for the expansion of stem cells directly inside the patient’s own bone marrow. Stem cells derived in this fashion would be far less likely to be rejected by the patient.  To paraphrase Abraham Lincoln, they would be “of the patient, by the patient and for the patient—and shall not perish from the patient”—sorry!

Several of the rats generated in Ying’s lab (to mimic human diseases) were so successful that they have been donated to the Rat Research Resource center so that other scientists can use them for their study.

“Maybe in the future we will develop a cure for some diseases because of knowledge from using rat models,” said Ying. “I think it’s very possible. So we want more researchers from USC and beyond to come and use this technology.”

And it all began with the humble rat…