Meet the people who are changing the future

Kristin MacDonald

Every so often you hear a story and your first reaction is “oh, I have to share this with someone, anyone, everyone.” That’s what happened to me the other day.

I was talking with Kristin MacDonald, an amazing woman, a fierce patient advocate and someone who took part in a CIRM-funded clinical trial to treat retinitis pigmentosa (RP). The disease had destroyed Kristin’s vision and she was hoping the therapy, pioneered by jCyte, would help her. Kristin, being a bit of a pioneer herself, was the first person to test the therapy in the U.S.

Anyway, Kristin was doing a Zoom presentation and wanted to look her best so she asked a friend to come over and do her hair and makeup. The woman she asked, was Rosie Barrero, another patient in that RP clinical trial. Not so very long ago Rosie was legally blind. Now, here she was helping do her friend’s hair and makeup. And doing it beautifully too.

That’s when you know the treatment works. At least for Rosie.

There are many other stories to be heard – from patients and patient advocates, from researchers who develop therapies to the doctors who deliver them. – at our CIRM 2020 Grantee Meeting on next Monday September 14th Tuesday & September 15th.

It’s two full days of presentations and discussions on everything from heart disease and cancer, to COVID-19, Alzheimer’s, Parkinson’s and spina bifida. Here’s a link to the Eventbrite page where you can find out more about the event and also register to be part of it.

Like pretty much everything these days it’s a virtual event so you’ll be able to join in from the comfort of your kitchen, living room, even the backyard.

And it’s free!

You can join us for all two days or just one session on one day. The choice is yours. And feel free to tell your friends or anyone else you think might be interested.

We hope to see you there.

Stem Cell All-Stars, All For You

goldstein-larry

Dr. Larry Goldstein, UC San Diego

It’s not often you get a chance to hear some of the brightest minds around talk about their stem cell research and what it could mean for you, me and everyone else. That’s why we’re delighted to be bringing some of the sharpest tools in the stem cell shed together in one – virtual – place for our CIRM 2020 Grantee Meeting.

The event is Monday September 14th and Tuesday September 15th. It’s open to anyone who wants to attend and, of course, it’s all being held online so you can watch from the comfort of your own living room, or garden, or wherever you like. And, of course, it’s free.

BotaDaniela2261

Dr. Daniela Bota, UC Irvine

The list of speakers is a Who’s Who of researchers that CIRM has funded and who also happen to be among the leaders in the field. Not surprising as California is a global center for regenerative medicine. And you will of course be able to post questions for them to answer.

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Dr. Deepak Srivastava, Gladstone Institutes

The key speakers include:

Larry Goldstein: the founder and director of the UCSD Stem Cell Program talking about Alzheimer’s research

Irv Weissman: Stanford University talking about anti-cancer therapies

Daniela Bota: UC Irvine talking about COVID-19 research

Deepak Srivastava: Gladsone Institutes, talking about heart stem cells

Other topics include the latest stem cell approaches to COVID-19, spinal cord injury, blindness, Parkinson’s disease, immune disorders, spina bifida and other pediatric disorders.

You can choose one topic or come both days for all the sessions. To see the agenda for each day click here. Just one side note, this is still a work in progress so some of the sessions have not been finalized yet.

And when you are ready to register go to our Eventbrite page. It’s simple, it’s fast and it will guarantee you’ll be able to be part of this event.

We look forward to seeing you there.

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. 

CIRM invests $1.3 million to study stem cells in metabolic liver disease

Grikscheit

Dr. Tracy Grikscheit. Image courtesy of Children’s Hospital LA.

Metabolic liver disease, is an emerging public health concern in Western countries, but has largely been overshadowed by health issues such as cancer and diabetes. Chronic liver disease (of which metabolic liver disease is a significant contributor) however, is a significant public health concern, evidenced by its contribution to nearly 2 million deaths per year worldwide.

The primary treatment option for metabolic liver disease is a liver transplant. In fact, of the liver transplants performed every year, 14% are due to damage associated with metabolic disorders. With any organ transplant, however, such a procedure comes with drawbacks, the most frustrating of which is the need for patients to wait for an organ donor.

As transplants are not a reasonable or feasible option for many people, alternative treatment options are necessary.  Enter Dr. Tracy Grikscheit, a doctor-scientist at the Children’s Hospital Los Angeles, who hopes to make liver transplant a thing of the past for the millions of people who live with metabolic liver disease.

Dr. Grikscheit was awarded a $1.3 million grant to study how stem cells can be used to treat liver disease caused by metabolic disorders. In a press release, Dr. Grikscheit details the importance and practicality of using stem cells to treat liver disease:

“Liver-based metabolic diseases are the perfect starting point to apply cellular therapy to liver disorders. The only current therapy — a liver transplant — is costly and in short supply. Plus, it requires suppressing the patient’s immune system, which has long-term consequences.”

The project, termed UPLiFT for Universal Pluripotent Stem Cell Therapy, aims to use pluripotent stem cells (cells that can turn into any cell in the body) to correct liver associated disorders like Crigler-Najjar Syndrome. A genetic mutation in liver cells of these patients makes them unable to covert bilirubin (a byproduct of red blood cell degradation) to its non-toxic form. Dr. Grikscheit hopes to bypass the need for a liver transplant by giving these patients pluripotent stem cells that can become liver cells without the genetic mutation, and are able to convert bilirubin to its non-toxic form. The use of pluripotent stem cells would also potentially eliminate the need for lifelong immunosuppressive therapy

Dr. Grikscheit will use the CIRM grant to test safety and efficacy of the stem cell treatment in pre-clinical trials to determine the optimal cell dosage that will be both safe and relieve disease symptoms, as well as assessing any off-target effects of the treatment. She has previously received a grant from CIRM to study stem cell therapy options for digestive neuromuscular condition, which you can read about here.

 

Living with sickle cell disease: one person’s story of pain and prejudice and their hopes for a stem cell therapy

Whenever we hold an in-person Board meeting at CIRM we like to bring along a patient or patient advocate to address the Board. Hearing from the people they are trying to help, who are benefiting or may benefit from a therapy CIRM is funding, reminds them of the real-world implications of the decisions they make and the impact they have on people’s lives.

At our most recent meeting Marissa Cors told her story.

Marissa at ICOC side view copy

Marissa Cors addressing the CIRM Board

My name is Marissa Cors, I have sickle cell disease. I was diagnosed with sickle cell disease at six months of age. I am now 40. Sickle cell has been a part of my life every day of my life.

The treatments you are supporting and funding here at CIRM are very important. They offer a potential cure to a disease that desperately needs one. I want to tell you just how urgently people with sickle cell need a cure.

I have been hospitalized so many times that my medical record is now more than 8 gigabytes. I have almost 900 pages in my medical record from my personal doctor alone.

I live with pain every day of my life but because you can’t see pain most people have no idea how bad it can be. The pain comes in two forms:

Chronic pain – this comes from the damage that sickle cell disease does to the body over many years. My right knee, my left clavicle, my lower back are all damaged because of the disease. I get chronic headaches. All these are the result of a lifetime of crisis.

Acute pain – this is the actual crisis that can’t be controlled, where the pain is so intense and the risk of damage to my organs so great that it requires hospitalization. That hospitalization can result in yet more pain, not physical but emotional and psychological pain.

But those are just the simple facts. So, let me tell you what it’s really like to live with sickle cell disease.

Marissa at ICOC front, smiling

It means being in a constant state of limbo and a constant state of unknown because you have no idea when the next crisis is going to come and take over and you have to stop your life. You have absolutely no idea how bad the pain will be or how long it will last.

It is a constant state of frustration and upset and even a constant state of guilt because it is your responsibility to put in place all the safety nets and plans order to keep life moving as normally as possible, not just for you but for everyone else around you. And you know that when a crisis comes, and those plans get ripped up that it’s not just your own life that gets put on hold while you try to deal with the pain, it’s the lives of those you love.

It means having to put your life on hold so often that it’s hard to have a job, hard to have a career or lead a normal life. Hard to do the things everyone else takes for granted. For example, in my 30’s, while all my friends from home and college were building careers and getting married and having families, I was in a cancer ward trying to stay alive, because that’s where they put you when you have sickle cell disease. The cancer ward.

People talk about new medications now that are more effective at keeping the disease under control. But let me tell you. As a black woman walking into a hospital Emergency Room saying I am having a sickle cell crisis and need pain medications, and then naming the ones I need, too often I don’t get treated as a patient, I get treated as a drug addict, a drug seeker.

Even when the doctors do agree to give me the medications I need they often act in a way that clearly shows they don’t believe me. They ask, “How do we know this is a crisis, why is it taking you so long for the medication to take effect?” These are people who spent a few days in medical school reading from a textbook about sickle cell disease. I have spent a lifetime living with it and apparently that’s still not enough for them to trust that I do know what I am talking about.

That’s when I usually say, “Goodbye and don’t forget to send in your replacement doctor because I can’t work with you.”

I have had doctors take away my medication because they wanted to see how I would react without it.

If I dare to question what a doctor or nurse does, they frequently tell me they have to go and take care of other patients who are really sick, not like me.

Even when I talk in my “nice white lady” voice they still treat me and call me “an angry black girl”. Girl. I’m a 40 year old woman but I get treated like a child.

It’s hard to be in the hospital surrounded by doctors and nurses and yet feel abandoned by the medical staff around you.

This month alone 25 people have died from sickle cell in the US. It’s not because we don’t have treatments that can help. It’s due to negligence, not getting the right care at the right time.

I know the work you do here at CIRM won’t change those attitudes. But maybe the research you support could find a cure for sickle cell, so people like me don’t have to endure the pain, the physical, emotional and spiritual pain, that the disease brings every day.

You can read about the work CIRM is funding targeting sickle cell disease, including two clinical trials, on this page on our website.

Stem Cell Agency Invests in New Immunotherapy Approach to HIV, Plus Promising Projects Targeting Blindness and Leukemia

HIV AIDS

While we have made great progress in developing therapies that control the AIDS virus, HIV/AIDS remains a chronic condition and HIV medicines themselves can give rise to a new set of medical issues. That’s why the Board of the California Institute for Regenerative Medicine (CIRM) has awarded $3.8 million to a team from City of Hope to develop an HIV immunotherapy.

The City of Hope team, led by Xiuli Wang, is developing a chimeric antigen receptor T cell or CAR-T that will enable them to target and kill HIV Infection. These CAR-T cells are designed to respond to a vaccine to expand on demand to battle residual HIV as required.

Jeff Sheehy

CIRM Board member Jeff Sheehy

Jeff Sheehy, a CIRM Board member and patient advocate for HIV/AIDS, says there is a real need for a new approach.

“With 37 million people worldwide living with HIV, including one million Americans, a single treatment that cures is desperately needed.  An exciting feature of this approach is the way it is combined with the cytomegalovirus (CMV) vaccine. Making CAR T therapies safer and more efficient would not only help produce a new HIV treatment but would help with CAR T cancer therapies and could facilitate CAR T therapies for other diseases.”

This is a late stage pre-clinical program with a goal of developing the cell therapy and getting the data needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial.

The Board also approved three projects under its Translation Research Program, this is promising research that is building on basic scientific studies to hopefully create new therapies.

  • $5.068 million to University of California at Los Angeles’ Steven Schwartz to use a patient’s own adult cells to develop a treatment for diseases of the retina that can lead to blindness
  • $4.17 million to Karin Gaensler at the University of California at San Francisco to use a leukemia patient’s own cells to develop a vaccine that will stimulate their immune system to attack and destroy leukemia stem cells
  • Almost $4.24 million to Stanford’s Ted Leng to develop an off-the-shelf treatment for age-related macular degeneration (AMD), the leading cause of vision loss in the elderly.

The Board also approved funding for seven projects in the Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.

Application Title Institution CIRM Committed Funding
DISC2-10979 Universal Pluripotent Liver Failure Therapy (UPLiFT)

 

Children’s Hospital of Los Angeles $1,297,512

 

DISC2-11105 Pluripotent stem cell-derived bladder epithelial progenitors for definitive cell replacement therapy of bladder cancer

 

Stanford $1,415,016
DISC2-10973 Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases

 

U.C. San Diego $1,160,648
DISC2-11070 Drug Development for Autism Spectrum Disorder Using Human Patient iPSCs

 

Scripps $1,827,576
DISC2-11183 A screen for drugs to protect against chemotherapy-induced hearing loss, using sensory hair cells derived by direct lineage reprogramming from hiPSCs

 

University of Southern California $833,971
DISC2-11199 Modulation of the Wnt pathway to restore inner ear function

 

Stanford $1,394,870
DISC2-11109 Regenerative Thymic Tissues as Curative Cell Therapy for Patients with 22q11 Deletion Syndrome

 

Stanford $1,415,016

Finally, the Board approved the Agency’s 2019 research budget. Given CIRM’s new partnership with the National Heart, Lung, Blood Institute (NHLBI) to accelerate promising therapies that could help people with Sickle Cell Disease (SCD) the Agency is proposing to set aside $30 million in funding for this program.

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Congresswoman Barbara Lee (D-CA 13th District)

“I am deeply grateful for organizations like CIRM and NHLBI that do vital work every day to help people struggling with Sickle Cell Disease,” said Congresswoman Barbara Lee (D-CA 13th District). “As a member of the House Appropriations Subcommittee on Labor, Health and Human Services, and Education, I know well the importance of this work. This innovative partnership between CIRM and NHLBI is an encouraging sign of progress, and I applaud both organizations for their tireless work to cure Sickle Cell Disease.”

Under the agreement CIRM and the NHLBI will coordinate efforts to identify and co-fund promising therapies targeting SCD.  Programs that are ready to start an IND-enabling or clinical trial project for sickle cell can apply to CIRM for funding from both agencies. CIRM will share application information with the NHLBI and CIRM’s Grants Working Group (GWG) – an independent panel of experts which reviews the scientific merits of applications – will review the applications and make recommendations. The NHLBI will then quickly decide if it wants to partner with CIRM on co-funding the project and if the CIRM governing Board approves the project for funding, the two organizations will agree on a cost-sharing partnership for the clinical trial. CIRM will then set the milestones and manage the single CIRM award and all monitoring of the project.

“This is an extraordinary opportunity to create a first-of-its-kind partnership with the NHLBI to accelerate the development of curative cell and gene treatments for patients suffering with Sickle Cell Disease” says Maria T. Millan, MD, President & CEO of CIRM. “This allows us to multiply the impact each dollar has to find relief for children and adults who battle with this life-threatening, disabling condition that results in a dramatically shortened lifespan.  We are pleased to be able to leverage CIRM’s acceleration model, expertise and infrastructure to partner with the NHLBI to find a cure for this condition that afflicts 100,000 Americans and millions around the globe.”

The budget for 2019 is:

Program type 2019
CLIN1 & 2

CLIN1& 2 Sickle Cell Disease

$93 million

$30 million

TRANSLATIONAL $20 million
DISCOVER $0
EDUCATION $600K

 

 

Friday Roundup: A better kind of blood stem cell transplant; Encouraging news from spinal cord injury trial; Finding an “elusive” cell that could help diabetics

Cool Instagram image of the week:

Pancreatic Progenitors

Diabetes Research Institute scientists have confirmed that the unique stem cells reside within large ducts of the human pancreas. Two such ducts (green) surrounded by three islets (white) are shown. [Diabetes Research Institute Foundation]

Chemo- and radiation-free blood stem cell transplant showing promise

Bubble baby disease, also known as severe combined immunodeficiency (SCID), is an inherited disorder that leaves newborns without an effective immune system. Currently, the only approved treatment for SCID is a blood stem cell transplant, in which the patient’s defective immune system cells are eliminated by chemotherapy or radiation to clear out space for cells from a healthy, matched donor. Even though the disease can be fatal, physicians loathe to perform a stem cell transplant on bubble baby patients:

Shizuru“Physicians often choose not to give chemotherapy or radiation to young children with SCID because there are lifelong effects: neurological impairment, growth delays, infertility, risk of cancer, etc.,” says Judith Shizuru, MD, PhD, professor of medicine at Stanford University.

To avoid these complications, Dr. Shizuru is currently running a CIRM-funded clinical trial testing a gentler approach to prepare patients for blood stem cell transplants. She presented promising, preliminary results of the trial on Tuesday at the annual meeting of Stanford’s Center for Definitive and Curative Medicine.

Trial participants are receiving a protein antibody called CD117 before their stem cell transplant. Previous studies in animals showed that this antibody binds to the surface of blood stem cells and blocks the action of a factor which is required for stem cell survival. This property of CD117 provides a means to get rid of blood stem cells without radiation or chemotherapy.

Early results in two participants indicate that, 6 and 9 months after receiving the CD117 blood stem cell transplants, the donor cells have successfully established themselves in the patients and begun making immune cells.

Spinal cord injury trial reports more promising results:

AsteriasRegular readers of our blog will already know about our funding for the clinical trial being run by Asterias Biotherapeutics to treat spinal cord injuries. The latest news from the company is very encouraging, in terms of both the safety and effectiveness of the treatment.

Asterias is transplanting stem cells into patients who have suffered recent injuries that have left them paralyzed from the neck down. It’s hoped the treatment will restore connections at the injury site, allowing patients to regain some movement and feeling in their hands and arms.

This week the company announced that of the 25 patients they have treated there have been no serious side effects. In addition:

  • Magnetic Resonance Imaging (MRI) scans show that in more than 90 percent of the patients the cells appear to show signs of engraftment
  • At least 75 percent of those treated have recovered at least one motor level, and almost 20 percent have recovered two levels

In a news release, Michael Mulroy, Asterias’ President and CEO, said:

“The positive safety profile to date, the evidence supporting engraftment of the cells post-implantation, and the improvements we are seeing in upper extremity motor function highlight the promising findings coming from this Phase 1/2a clinical trial, which will guide us as we work to design future studies.”

There you are! Finding the “elusive” human pancreatic progenitor cells – the story behind our cool Instagram image of the week.

Don’t you hate it when you lose something and can’t find it? Well imagine the frustration of scientists who were looking for a group of cells they were sure existed but for decades they couldn’t locate them. Particularly as those cells might help in developing new treatments for diabetes.

Diabetes-Research-Institute_University-of-Miami-Miller-School-of-MedicineWell, rest easy, because scientists at the Diabetes Research Institute at the University of Miami finally found them.

In a study, published in Genetic Engineering and Biotechnology News, the researchers show how they found these progenitor cells in the human pancreas, tucked away in the glands and ducts of the organ.

In type 1 diabetes, the insulin-producing cells in the pancreas are destroyed. Finding these progenitor cells, which have the ability to turn into the kinds of cells that produce insulin, means researchers could develop new ways to regenerate the pancreas’ ability to function normally.

That’s a long way away but this discovery could be an important first step along that path.

CHLA study explains how stem cells slow progression of kidney disorder

Not all stem cell-based therapies act by replacing diseased or damaged cells. Many treatments in clinical development rely on the injected stem cells releasing proteins which trigger the slow down or even reversal of damage caused by disease or injury. A new CIRM-funded study that’s developing a stem cell therapy for a rare kidney disease uncovered a similar mechanism but with an intriguing twist. The research, published this week in Scientific Reports, suggests that the stem cells shed tiny vesicles that essentially act like sponges by trapping proteins thought to be responsible for damaging the kidney.

Amniotic fluid stem cells: a promising approach to treating kidney disease

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Network of blood-filtering blood vessels in the kidney. Image: Wikipedia

In previous studies the research team, from the Saban Research Institute of Children’s Hospital Los Angeles (CHLA), had shown that amniotic fluid stem cells can help slow the progress of Alport syndrome when injected into the kidneys of mice engineered to mimic symptoms of the disease. Alport syndrome is a genetic disease that damages the kidney’s capillaries – tiny blood vessels – which help filter the body’s blood supply. This progressive damage causes blood and proteins to leak into the urine, and leads to high blood pressure and swelling in the legs and around the eyes.

Cells in the kidney release a protein called VEGF, a stimulator of new blood vessel growth, which plays an important role in maintaining just the right balance of capillaries within the blood-filtering structures of the kidney. Excessive levels of VEGF have been associated with many diseases including kidney disorders like Alport syndrome. Although the protective effects of amniotic fluid stem cells in the mouse model of Alport syndrome were not understood, the CHLA team suspected that the cells could be interfering with the effects of the extra VEGF.

Extracellular vesicles: just another trick that nature has up its sleeve
Specifically, the scientists examined whether so-called extracellular vesicles released from the stem cells are responsible for reducing VEGF activity and slowing the disease. These vesicles are tiny pieces of cell membrane that bud off from the stem cell and carry along proteins and other cell components. Scientists used to think the vesicles were just cellular discards but countless studies have established that they actually play an important role in communication between cells.

The team showed that the vesicles released by amniotic fluid stem cells contained receptors for VEGF. When those vesicles were added to a petri dish containing VEGF and kidney blood vessel cells, the vesicles reduced the VEGF activity and protected the cells from damage. But when vesicles from stem cells lacking the VEGF receptors were used, that protection was lost. First author Sargis Sedrakyan, PhD summed up the results in a press release:

“We have demonstrated that these vesicles can be used to regulate VEGF activity and prevent the [kidney] capillary damage. We can efficiently use the vesicles to help restore normal kidney function by curbing the progression of endothelial damage in the filtration unit of the kidney.”

Back in 2013, first author Sargis Sedrakyan summarized his research in this 30 second video for the CIRM Grantee Elevator Pitch Challenge. 

Vesicles from aminotic fluid stem cells beat out FDA-approved VEGF blocker
Now anti-VEGF antibody proteins that can tightly bind and inhibit VEGF are readily available and have even been approved by the Food and Drug Administration for other disorders. So why even bother with these vesicles as a possible therapeutic strategy for Alport syndrome? Well, in side-by-side comparisons, it turns out the stem cell-derived vesicles, but not the anti-VEGF antibodies, could not only trap the VEGF but also put the brakes on VEGF production. So, it seems that the vesicles have additional properties that could make them more ideal than current approaches.

And as indicated in the press release, the CHLA team is eager to continue exploring this therapeutic strategy:

“The team’s next step will be to validate the stem cell-derived vesicle in different types of kidney disease with the final aim of finding a therapy that is effective for all patients who suffer from chronic kidney disease.”

 

CIRM Board invests in three new stem cell clinical trials targeting arthritis, cancer and deadly infections

knee

Arthritis of the knee

Every day at CIRM we get calls from people looking for a stem cell therapy to help them fight a life-threatening or life-altering disease or condition. One of the most common calls is about osteoarthritis, a painful condition where the cartilage that helps cushion our joints is worn away, leaving bone to rub on bone. People call asking if we have something, anything, that might be able to help them. Now we do.

At yesterday’s CIRM Board meeting the Independent Citizens’ Oversight Committee or ICOC (the formal title of the Board) awarded almost $8.5 million to the California Institute for Biomedical Research (CALIBR) to test a drug that appears to help the body regenerate cartilage. In preclinical tests the drug, KA34, stimulated mesenchymal stem cells to turn into chondrocytes, the kind of cell found in healthy cartilage. It’s hoped these new cells will replace those killed off by osteoarthritis and repair the damage.

This is a Phase 1 clinical trial where the goal is primarily to make sure this approach is safe in patients. If the treatment also shows hints it’s working – and of course we hope it will – that’s a bonus which will need to be confirmed in later stage, and larger, clinical trials.

From a purely selfish perspective, it will be nice for us to be able to tell callers that we do have a clinical trial underway and are hopeful it could lead to an effective treatment. Right now the only alternatives for many patients are powerful opioids and pain killers, surgery, or turning to clinics that offer unproven stem cell therapies.

Targeting immune system cancer

The CIRM Board also awarded Poseida Therapeutics $19.8 million to target multiple myeloma, using the patient’s own genetically re-engineered stem cells. Multiple myeloma is caused when plasma cells, which are a type of white blood cell found in the bone marrow and are a key part of our immune system, turn cancerous and grow out of control.

As Dr. Maria Millan, CIRM’s President & CEO, said in a news release:

“Multiple myeloma disproportionately affects people over the age of 65 and African Americans, and it leads to progressive bone destruction, severe anemia, infectious complications and kidney and heart damage from abnormal proteins produced by the malignant plasma cells.  Less than half of patients with multiple myeloma live beyond 5 years. Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

In a news release from Poseida, CEO Dr. Eric Ostertag, said the therapy – called P-BCMA-101 – holds a lot of promise:

“P-BCMA-101 is elegantly designed with several key characteristics, including an exceptionally high concentration of stem cell memory T cells which has the potential to significantly improve durability of response to treatment.”

Deadly infections

The third clinical trial funded by the Board yesterday also uses T cells. Researchers at Children’s Hospital of Los Angeles were awarded $4.8 million for a Phase 1 clinical trial targeting potentially deadly infections in people who have a weakened immune system.

Viruses such as cytomegalovirus, Epstein-Barr, and adenovirus are commonly found in all of us, but our bodies are usually able to easily fight them off. However, patients with weakened immune systems resulting from chemotherapy, bone marrow or cord blood transplant often lack that ability to combat these viruses and it can prove fatal.

The researchers are taking T cells from healthy donors that have been genetically matched to the patient’s immune system and engineered to fight these viruses. The cells are then transplanted into the patient and will hopefully help boost their immune system’s ability to fight the virus and provide long-term protection.

Whenever you can tell someone who calls you, desperately looking for help, that you have something that might be able to help them, you can hear the relief on the other end of the line. Of course, we explain that these are only early-stage clinical trials and that we don’t know if they’ll work. But for someone who up until that point felt they had no options and, often, no hope, it’s welcome and encouraging news that progress is being made.