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. 

Boosting the blood system after life-saving therapy

Following radiation, the bone marrow shows nearly complete loss of blood cells in mice (left). Mice treated with the PTP-sigma inhibitor displayed rapid recovery of blood cells (purple, right): Photo Courtesy UCLA

Chemotherapy and radiation are two of the front-line weapons in treating cancer. They can be effective, even life-saving, but they can also be brutal, taking a toll on the body that lasts for months. Now a team at UCLA has developed a therapy that might enable the body to bounce back faster after chemo and radiation, and even make treatments like bone marrow transplants easier on patients.

First a little background. Some cancer treatments use chemotherapy and radiation to kill the cancer, but they can also damage other cells, including those in the bone marrow responsible for making blood stem cells. Those cells eventually recover but it can take weeks or months, and during that time the patient may feel fatigue and be more susceptible to infections and other problems.

In a CIRM-supported study, UCLA’s Dr. John Chute and his team developed a drug that speeds up the process of regenerating a new blood supply. The research is published in the journal Nature Communications.

They focused their attention on a protein called PTP-sigma that is found in blood stem cells and acts as a kind of brake on the regeneration of those cells. Previous studies by Dr. Chute showed that, after undergoing radiation, mice that have less PTP-sigma were able to regenerate their blood stem cells faster than mice that had normal levels of the protein.

John Chute: Photo courtesy UCLA

So they set out to identify something that could help reduce levels of PTP-sigma without affecting other cells. They first identified an organic compound with the charming name of 6545075 (Chembridge) that was reported to be effective against PTP-sigma. Then they searched a library of 80,000 different small molecules to find something similar to 6545075 (and this is why science takes so long).

From that group they developed more than 100 different drug candidates to see which, if any, were effective against PTP-sigma. Finally, they found a promising candidate, called DJ009. In laboratory tests DJ009 proved itself effective in blocking PTP-sigma in human blood stem cells.

They then tested DJ009 in mice that were given high doses of radiation. In a news release Dr. Chute said the results were very encouraging:

“The potency of this compound in animal models was very high. It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”

Of the radiated mice, most that were given DJ009 survived. In comparison, those that didn’t get DJ009 died within three weeks.

They saw similar benefits in mice given chemotherapy. Mice with DJ009 saw their white blood cells – key components of the immune system – return to normal within two weeks. The untreated mice had dangerously low levels of those cells at the same point.

It’s encouraging work and the team are already getting ready for more research so they can validate their findings and hopefully take the next step towards testing this in people in clinical trials.

Stem cell progress and promise in fighting leukemia

Computer illustration of a cancerous white blood cell in leukemia.

There is nothing you can do to prevent or reduce your risk of leukemia. That’s not a very reassuring statement considering that this year alone almost 62,000 Americans will be diagnosed with leukemia; almost 23,000 will die from the disease. That’s why CIRM is funding four clinical trials targeting leukemia, hoping to develop new approaches to treat, and even cure it.

That’s also why our next special Facebook Live “Ask the Stem Cell Team” event is focused on this issue. Join us on Thursday, August 29th from 1pm to 2pm PDT to hear a discussion about the progress in, and promise of, stem cell research for leukemia.

We have two great panelists joining us:

Dr. Crystal Mackall, has many titles including serving as the Founding Director of the Stanford Center for Cancer Cell Therapy.  She is using an innovative approach called a Chimeric Antigen Receptor (CAR) T Cell Therapy. This works by isolating a patient’s own T cells (a type of immune cell) and then genetically engineering them to recognize a protein on the surface of cancer cells, triggering their destruction. This is now being tested in a clinical trial funded by CIRM.

Natasha Fooman. To describe Natasha as a patient advocate would not do justice to her experience and expertise in fighting blood cancer and advocating on behalf of those battling the disease. For her work she has twice been named “Woman of the Year” by the Leukemia and Lymphoma Society. In 2011 she was diagnosed with a form of lymphoma that was affecting her brain. Over the years, she would battle lymphoma three times and undergo chemotherapy, radiation and eventually a bone marrow transplant. Today she is cancer free and is a key part of a CIRM team fighting blood cancer.

We hope you’ll join us to learn about the progress being made using stem cells to combat blood cancers, the challenges ahead but also the promising signs that we are advancing the field.

We also hope you’ll take an active role by posting questions on Facebook during the event, or sending us questions ahead of time to info@cirm.ca.gov. We will do our best to address as many as we can.

Here’s the link to the event, feel free to share this with anyone you think might be interested in joining us for Facebook Live “Ask the Stem Cell Team about Leukemia”

Antibody effective in cure for rare blood disorders

3D illustration of an antibody binding to a designated target.
Illustration created by Audra Geras.

A variety of diseases can be traced to a simple root cause: problems in the bone marrow. The bone marrow contains specialized stem cells known as hematopoietic stem cells (HSCs) that give rise to different types of blood cells. As mentioned in a previous blog about Sickle Cell Disease (SCD), one problem that can occur is the production of “sickle like” red blood cells. In blood cancers like leukemia, there is an uncontrollable production of abnormal white blood cells. Another condition, known as myelodysplastic syndromes (MDS), are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells.

For diseases that originate in the bone marrow, one treatment involves introducing healthy HSCs from a donor or gene therapy. However, before this type of treatment can take place, all of the problematic HSCs must be eliminated from the patient’s body. This process, known as pre-treatment, involves a combination of chemotherapy and radiation, which can be extremely toxic and life threatening. There are some patients whose condition has progressed to the point where their bodies are not strong enough to withstand pre-treatment. Additionally, there are long-term side effects that chemotherapy and radiation can have on infant children that are discussed in a previous blog about pediatric brain cancer.

Could there be a targeted, non-toxic approach to eliminating unwanted HSCs that can be used in combination with stem cell therapies? Researchers at Stanford say yes and have very promising results to back up their claim.

Dr. Judith Shizuru and her team at Stanford University have developed an antibody that can eliminate problematic blood forming stem cells safely and efficiently. The antibody is able to identify a protein on HSCs and bind to it. Once it is bound, the protein is unable to function, effectively removing the problematic blood forming stem cells.

Dr. Shizuru is the senior author of a study published online on February 11th, 2019 in Blood that was conducted in mice and focused on MDS. The results were very promising, demonstrating that the antibody successfully depleted human MDS cells and aided transplantation of normal human HSCs in the MDS mouse model.

This proof of concept holds promise for MDS as well as other disease conditions. In a public release from Stanford Medicine, Dr. Shizuru is quoted as saying, “A treatment that specifically targets only blood-forming stem cells would allow us to potentially cure people with diseases as varied as sickle cell disease, thalassemia, autoimmune disorders and other blood disorders…We are very hopeful that this body of research is going to have a positive impact on patients by allowing better depletion of diseased cells and engraftment of healthy cells.”

The research mentioned was partially funded by us at CIRM. Additionally, we recently awarded a $3.7 million dollar grant to use the same antibody in a human clinical trial for the so-called “bubble baby disease”, which is also known as severe combined immunodeficiency (SCID). You can read more about that award on a previous blog post linked here.

New hope for stem cell therapy in patients with leukemia

LeukemiaWhiteBloodCell

Leukemia white blood cell

Of the many different kinds of cancer that affect humans, leukemia is the most common in young people. As with many types cancer, doctors mostly turn to chemotherapy to treat patients. Chemotherapy, however, comes with its own share of issues, primarily severe side effects and the constant threat of disease recurrence.

Stem cell therapy treatment has emerged as a potential cure for some types of cancer, with leukemia patients being among the first groups of patients to receive this type of treatment. While exciting because of the possibility of a complete cure, stem cell therapy comes with its own challenges. Let’s take a closer look.

Leukemia is characterized by abnormal white blood cells (also known as the many different types of cells that make up our immune system) that are produced at high levels. Stem cell therapy is such an appealing treatment option because it involves replacing the patient’s aberrant blood stem cells with healthy ones from a donor, which provides the possibility of complete and permanent remission for the patient.

Unfortunately, in approximately half of patients who receive this therapy, the donor cells (which turn into immune cells), can also destroy the patients healthy tissue (i.e. liver, skin etc…), because the transplanted blood stem cells recognize patient’s tissue as foreign. While doctors try to lessen this type of response (also known as graft versus host disease (GVHD)), by suppressing the patient’s immune system, this procedure lessens the effectiveness of the stem cell therapy itself.

Now scientists at the University of Zurich have made an important discovery – published in the journal Science Translational Medicine – that could mitigate this potentially fatal response in patients. They found that a molecule called GM-CSF, is a critical mediator of the severity of GVHD. Using a mouse model, they showed that if the donor cells were unable to produce GM-CSF, then mice fared significantly better both in terms of less damage to tissues normally affected by GVHD, such as the skin, and overall survival.

While exciting, the scientists were concerned about narrowing in on this molecule as a potential target to lessen GVHD, because GM-CSF, an important molecule in the immune system, might also be important for ensuring that the donor immune cells do their jobs properly. Reassuringly, the researchers found that blocking GM-CSF’s function had no effect on the ability of the donor cells to exert their anti-cancer effect. This was surprising because previously the ability of donor cells to cause GVHD, versus protect patients from the development of cancer was thought to occur via the same biological mechanisms.

Most excitingly, however, was that finding that high levels of GM-CSF are also observed in patient samples, and that the levels of GM-CSF correlate to the severity of GVHD. Dr. Burkhard Becher and his colleagues, the authors of this study, now want to run a clinical trial to determine whether blocking GM-CSF blocks GVHD in humans like it does in mice. In a press release, Dr. Becher states the importance of these findings:

“If we can stop the graft-versus-host response while preserving the anti-cancer effect, this procedure can be employed much more successfully and with fewer risks to the patient. This therapeutic strategy holds particular promise for patients with the poorest prognosis and highest risk of fatality.”

Surprise findings about bone marrow transplants could lead to more effective stem cell therapies

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Bone marrow transplant: Photo courtesy FierceBiotech

Some medical therapies have been around for so long that we naturally assume we understand how they work. That’s not always the case. Take aspirin for example. It’s been used for more than 4,000 years to treat pain and inflammation but it was only in the 1970’s that we really learned how it works.

The same is now true for bone marrow transplants. Thanks to some skilled research at the Fred Hutchinson Cancer Research Center in Seattle.

Bone marrow transplants have been used for decades to help treat deadly blood cancers such as leukemia and lymphoma. The first successful bone marrow transplant was in the late 1950’s, involving identical twins, one of whom had leukemia. Because the twins shared the same genetic make-up the transplant avoided potentially fatal problems like graft-vs-host-disease, where the transplanted cells attack the person getting them. It wasn’t until the 1970’s that doctors were able to perform transplants involving people who were not related or who did not share the same genetic make-up.

In a bone marrow or blood stem cell transplant, doctors use radiation or chemotherapy to destroy the bone marrow in a patient with, say, leukemia. Then cancer-free donor blood stem cells are transplanted into the patient to help create a new blood system, and rebuild their immune system.

Surprise findings

In the study, published in the journal Science Translational Medicine, the researchers were able to isolate a specific kind of stem cell that helps repair and rebuild the blood and immune system.

The team found that a small subset of blood stem cells, characterized by having one of three different kinds of protein on their surface – CD34 positive, CD45RA negative and CD90 positive – did all the work.

In a news release Dr. Hans-Peter Kiem, a senior author on the study, says some of their initial assumptions about how bone marrow transplants work were wrong:

“These findings came as a surprise; we had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”

Tracking the cells

The team performed bone-marrow transplants on monkeys and then followed those animals over the next seven years, observing what happened as the donor cells grew and multiplied.

They tracked hundreds of thousands of cells in the blood and found that, even though the cells with those three proteins on the surface made up just five percent of the total blood supply, they were responsible for rebuilding the entire blood and immune system.

Study co-author Dr. Jennifer Adair said they saw evidence of this rebuilding within 10 days of the transplant:

“Our ability to track individual blood cells that developed after transplant was critical to demonstrating that these really are stem cells.”

Hope for the future

It’s an important finding because it could help researchers develop new ways of delivering bone marrow transplants that are both safer and more effective. Every year some 3,000 people die because they cannot find a matching donor. Knowing which stem cells are specifically responsible for an effective transplant could help researchers come up with ways to get around that problem.

Although this work was done in monkeys, the scientists say humans have similar kinds of stem cells that appear to act in the same way. Proving that’s the case will obviously be the next step in this research.

 

Stem cell stories that caught our eye: a surprising benefit of fasting, faster way to make iPSCs, unlocking the secret of leukemia cancer cells

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Fasting

Is fasting the fountain of youth?

Among the many insults our bodies endure in old age is a weakened immune system which leaves the elderly more susceptible to infection. Chemotherapy patients also face the same predicament due to the immune suppressing effects of their toxic anticancer treatments. While many researchers aim to develop drugs or cell therapies to protect the immune system, a University of Southern California research report this week suggests an effective alternative intervention that’s startlingly straightforward: fasting for 72 hours.

The study published in Cell Stem Cell showed that cycles of prolonged fasting in older mice led to a decrease in white blood cells which in turn set off a regenerative burst of blood stem cells. This restart of the blood stem cells replenished the immune system with new white blood cells. In a pilot Phase 1 clinical trial, cancer patients who fasted 72 hours before receiving chemotherapy maintained normal levels of white blood cells.

A look at the molecular level of the process pointed to a decrease in the levels of a protein called PKA in stem cells during the fasting period. In a university press release carried by Science Daily, the study leader, Valter Longo, explained the significance of this finding:

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system. And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”

In additional to necessary follow up studies, the team is looking into whether fasting could benefit other organ systems besides the immune system. If the data holds up, it could be that regular fasting or direct targeting of PKA could put us on the road to a much more graceful and healthier aging process.

4955224186_31f969e6fd_m

Faster, cheaper, safer way to use iPS cells

Science, like traffic in any major city, never moves quite as quickly as you would like, but now Japanese researchers are teaming up to develop a faster, and cheaper way of using iPSC’s , pluripotent stem cells that are reprogrammed from adult cells, for transplants.

Part of the beauty of iPSCs is that because those cells came from the patient themselves, there is less risk of rejection. But there are problems with this method. Taking adult cells and turning them into enough cells to treat someone can take a long time. It’s expensive too.

But now researchers at Kyoto University and three other institutions in Japan have announced they are teaming up to change that. They want to create a stockpile of iPSCs that are resistant to immunological rejection, and are ready to be shipped out to researchers.

Having a stockpile of ready-to-use iPSCs on hand means researchers won’t have to wait months to develop their own, so they can speed up their work.

Shinya Yamanaka, who developed the technique to create iPSCs and won the Nobel prize for his efforts, say there’s another advantage with this collaboration. In a news article on Nikkei’s Asian Review he said these cells will have been screened to make sure they don’t carry any potentially cancer-causing mutations.

“We will take all possible measures to look into the safety in each case, and we’ll give the green light once we’ve determined they are sound scientifically. If there is any concern at all, we will put a stop to it.”

CIRM is already working towards a similar goal with our iPSC Initiative.

Unlocking the secrets of leukemia stem cells

the-walking-dead-season-6-zombies

Zombies: courtesy “The Walking Dead”

Any article that has an opening sentence that says “Cancer stem cells are like zombies” has to be worth reading. And a report in ScienceMag  that explains how pre-leukemia white blood cell precursors become leukemia cancer stem cells is definitely worth reading.

The article is about a study in the journal Cell Stem Cell by researchers at UC San Diego. The senior author is Catriona Jamieson:

“In this study, we showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down.”

An enzyme called ADAR1 is known to spur cancer growth by manipulating small pieces of genetic material known as microRNA. Jamieson and her team wanted to track how that was done. They discovered it is a cascade of events, and that once the first step is taken a series of others quickly followed on.

They found that when white blood cells have a genetic mutation that is linked to leukemia, they are prone to inflammation. That inflammation then activates ADAR1, which in turn slows down a segment of microRNA called let-7 resulting in increased cell growth. The end result is that the white blood cells that began this cascade become leukemia stem cells and spread an aggressive and frequently treatment-resistant form of the blood cancer.

Having uncovered how ADAR1 works Jamieson and her team then tried to find a way to stop it. They discovered that by blocking the white blood cells susceptibility to inflammation, they could prevent the cascade from even starting. They also found that by using a compound called 8-Aza they could impede ADAR1’s ability to stimulate cell growth by around 40 percent.

Jamieson

Catriona Jamieson – definitely not a zombie

Jamieson says the findings open up all sorts of possibilities:

“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed.”

This wasn’t a CIRM-funded study but we have supported other projects by Dr. Jamieson that have led to clinical trials.

 

 

 

 

Chemo-Induced Heart Failure: Using Stem Cells to Identify Those at Risk

The good news is you’re cancer free, the bad news is you need a heart transplant.

It almost sounds like the punchline to a joke, but it’s no laugher matter because the scenario is real for some cancer patients.  Chemotherapy is a life saver for many but certain doses can be so toxic that it’s often hard to tell which symptoms are due to the cancer and which are due to the drug. Doxorubicin, used to treat around 50% of people diagnosed with breast cancer, is particularly awful. It’s been estimated that about 8% of those treated with doxorubicin experience side effects to the heart with symptoms ranging from arrhythmias to congestive heart failure severe enough to require heart transplantation.

800px-Doxorubicin_3D_ball

doxorubicin, a chemotherapy drug that carries a risk of serious heart damage

Avoiding the fire after jumping out of the frying pan
To avoid this predicament, doctors need a way to screen for an increased risk of heart damage due to doxorubicin before a patient even sets foot in a chemotherapy clinic. A CIRM-funded Stanford research team has made a big step toward that goal. Reporting yesterday in Nature Medicine, the scientists describe a non-invasive laboratory method that could help pinpoint which breast cancer patients are most likely to experience so-called doxorubicin-induced cardiotoxicity, or DIC.

Eight woman with breast cancer who had received doxorubicin treatment were recruited for the study. Four suffered from DIC while the other four did not. Skin samples were obtained from each person as well as four healthy volunteers. In the lab, the skin fibroblasts were reprogrammed into embryonic-like induced pluripotent stem cells (iPS) and then specialized into beating heart muscle cells or cardiomyocytes.

Chemo-induced heart damage in a dish
To find out if these patient-derived heart cells in the lab reflect what happened inside the patients’ hearts, the team compared the effects of doxorubicin on the different groups of cells. Looking at cell survival and the rhythmic beating of the heart cells, differences emerged. Lead author Paul Burridge summarized the results in a university press release:

“We found that cells from the patients who had experienced doxorubicin toxicity responded more negatively to the presence of the drug. They beat more irregularly in response to increased levels of doxorubicin, and we saw a significant increase in cell death after 72 hours of exposure to the drug when we compared those cells to cells from healthy controls or patients who didn’t have heart damage.”

Screen Shot 2016-04-19 at 9.27.23 AM

iPS-derived heart muscle cells from patients without (DOX, first row) and with (DOXTOX, bottom row) doxorubicin toxicity were treated with increasing amounts of the doxorubicin. The regular green stripe patterns indicate normal, intact muscle structures. By 0.1 µM of drug (second column), the DOXTOX structures become disarrayed while the DOX cells remain intact. Image: Burridge et al. Nat Med. 2016 Apr 18.

So how exactly does doxorubicin wreak havoc on the heart and why are some patients more sensitive to the drug?

Feeling the burn of reactive oxygen species (ROS)
The answers, in part, lie inside cellular structures called mitochondria where calories, stored in the form of sugar and fat, are “burned” to generate the body’s energy needs.  A harmful byproduct of this energy metabolism is reactive oxygen species (ROS), a chemically reactive form of oxygen that damages the mitochondria and other cell components. This damage is especially bad for heart cells which are 35% mitochondria by volume due to their intense energy needs as they busily beat for a lifetime.

Now, earlier research studies had pointed to ROS production in mitochondria as a key deliverer of doxorubicin’s destructive effects on the hearts of chemotherapy patients. So the Stanford team investigated the drug’s effects on ROS production and on mitochondria function in context of their patient derived heart cells. In response to doxorubicin, the scientists found that the cells from patients with doxorubicin induced heart damage generated more ROS compared to the cells from patients who had no heart damage. Along with the higher ROS production, mitochondria function was more compromised in the doxorubicin-sensitive heart cells.

And even in the absence of treatment, there was a lower baseline function and quantity of mitochondria in the doxorubicin-sensitive cells. These results suggest some underlying genetic differences in the heart muscle cells of patients with DIC. The team plans to perform DNA comparisons to pinpoint the genes involved and ultimately help patients survive cancer without the fear of swapping it for another life threatening illness.

iPS cells: opening new paths for helping cancers patients
Compared to tools he had previously relied on, Joseph Wu, the team leader and director of the Stanford’s Cardiovascular Institute, is very excited about his lab’s future research possibilities:

“In the past, we’ve tried to model this doxorubicin toxicity in mice by exposing them to the drug and then removing the heart for study. Now we can continue our studies in human cells with iPS-derived heart muscle cells from real patients. One day we may even be able to predict who is likely to get into trouble.”

Combination Cancer Therapy Gives Cells a Knockout Punch

For some forms of cancer, there really is no way to truly eradicate it. Even the most advanced chemotherapy treatments leave behind some straggler cells that can fuel a relapse.

By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable. [Credit: Aaron Goldman]

By hitting breast cancer cells with a targeted therapeutic immediately after chemotherapy, researchers were able to target cancer cells during a transitional stage when they were most vulnerable.
[Credit: Aaron Goldman]

But now, scientists have devised a unique strategy, something they are calling a ‘one-two punch’ that can more effectively wipe out dangerous tumors, and lower the risk of them ever returning for a round two.

Reporting in the latest issue of the journal Nature Communications, bioengineers at Brigham and Women’s Hospital (BWH) in Boston describe how treating breast cancer cells with a targeted drug immediately after chemotherapy was effective at killing the cancer cells and preventing a recurrence. According to lead scientist Shiladitya Sengupta, these findings were wholly unexpected:

“We were studying the fundamentals of how [drug] resistance develops and looking to understand what drives [cancer] relapse. What we found is a new paradigm for thinking about chemotherapy.”

In recent years, many scientists have suggested cancer stem cells are one of the biggest hurdles to curing cancer. Cancer stem cells are proposed to be a subpopulation of cancer cells that are resistant to chemotherapy. As a result, they can propagate the cancer after treatment, leading to a relapse.

In this work, Sengupta and his colleagues treated breast cancer cells with chemotherapy. And here is where things started getting interesting.

After chemotherapy, the breast cancer cells began to morph into cells that bore a close resemblance to cancer stem cells. For a brief period of time after treatment, these cells were neither fully cancer cells, nor fully stem cells. They were in transition.

The team then realized that because these cells were in transition, they may be more vulnerable to attack. Testing this hypothesis in mouse models of breast cancer, the team first zapped the tumors with chemotherapy. And, once the cells began to morph, they then blasted them with a different type of drug. The tumors never grew back, and the mice survived.

Interestingly, the team did not have similar success when they altered the timing of when they administered the therapy. Treating the mice with both types of drugs simultaneously didn’t have the same effect. Neither did increasing the time between treatments. In order to successfully treat the tumor they had a very slim window of opportunity.

“By treating with chemotherapy, we’re driving cells through a transition state and creating vulnerabilities,” said Aaron Goldman, the study’s first author. “This opens up the door: we can then try out different combinations and regimens to find the most effective way to kill the cells and inhibit tumor growth.”

In order to test these combinations, the researchers developed an ‘explant,’ a mini-tumor derived from a patient’s biopsy that can be grown in an environment that closely mimics its natural surroundings. The ultimate goal, says Goldman, is to map the precise order and timing of this treatment regimen in order to move toward clinical trials:

“Our goal is to build a regimen that will be [effective] for clinical trials. Once we’ve understood specific timing, sequence of drug delivery and dosage better, it will be easier to translate these findings clinically.”

Clever Stem Cells Withstand Chemo Drug’s Harmful Side Effects

For some conditions, it seem that the treatment can cause almost as many problems as than the disease itself. That’s often the case with some forms of cancer, such as acute lymphoblastic leukemia.

The most common type of cancer to affect children, treatment usually involves chemotherapy with the drug methotrexate (MTX). And, while effective at destroying the deadly cancer cells circulating in the patients’ blood, it also does significant damage to another part of the body: the bone.

Scientists have long sought a method that helps patients recover more quickly from the harmful effects of chemotherapy.

Scientists have long sought a method that helps patients recover more quickly from the harmful effects of chemotherapy.

But new research from Brown University’s Dr. Eric Darling and his team has found that not all types of bone cells are equally at risk of being damaged by MTX. In fact, one type may actually be impervious to the drug’s negative effects. These findings, published last week in the journal Experimental Cell Research, are especially important as doctors look to ways that help the youngest, most vulnerable cancer patients heal faster after treatment—regaining bone strength that can take them into a healthy adulthood.

As Olivia Beane, a graduate student in the Darling Lab and the lead author of this paper, explained in a news release:

“Kids undergo chemotherapy at such an important time when they should be growing, but instead they are introduced to this very harsh environment where bone cells are damaged with these drugs. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

The cell type Beane is referring to are called adipose-derived stem cells, or ASCs, which normally mature from this early, stem cell state into several types of mature cells, including bone tissue. Initially, Beane had been researching the basic properties of ASCs. But during her experiments she discovered that ASCs, unlike other stem cell types that mature into bone, appear to survive MTX. Now they just needed to understand why.

Further experiments revealed the underlying strengths of ASCs in resisting MTX’s effects. Normally, MTX works by binding to and shutting down a protein in the cell called dihydrofolate reductase, which is normally involved in synthesizing DNA. With DNA production shut down, cells can’t divide and multiply—which is great for killing harmful cancer cells, but potentially harmful as it can also destroy cells it shouldn’t.

However, ASCs are a little bit different. When coming into contact with MTX, these cells ramp up the DNA-promoting dihydrofolate reductase, producing more than enough to overcome a normal dose of MTX.

This discovery has raised some intriguing possibilities for treating MTX’s side effects. As Darling explained:

“Chemotherapies do a great job of killing cells and killing the cancer, and that’s what you want. But then there is a stage after that where you need to do recovery and regeneration.”

And while the results of this study are preliminary, the researchers are cautiously optimistic that the MTX-resistant properties of ASCs could be the key to fast tracking recovery times.

The first step, Darling adds, is to save a life. And MTX has done that for countless children afflicted by cancer. But the cost of saving that life should also be taken into account—so that these children who have already been through so much may one day not need to worry about long, healthy lives as they mature into adults.

Want to learn more about how CIRM-funded researchers are developing new tools to fight all types of leukemia? Check out our Leukemia Fact Sheet.

Anne Holden