Way back in 2013, the CIRM Board invested $32 million in a project to create an iPSC Bank. The goal was simple; to collect tissue samples from people who have different diseases, turn those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells (iPSC) – and create a facility where those lines can be stored and distributed to researchers who need them.
Fast forward almost seven years and that idea has now become the largest public iPSC bank in the world. The story of how that happened is the subject of a great article (by CIRM’s Dr. Stephen Lin) in the journal Science Direct.
Dr. Stephen Lin
In 2013 there was a real need for the bank. Scientists around the world were doing important research but many were creating the cells they used for that research in different ways. That made it hard to compare one study to another and come up with any kind of consistent finding. The iPSC Bank was designed to change that by creating one source for high quality cells, collected, processed and stored under a single, consistent method.
Tissue samples – either blood or skin – were collected from thousands of individuals around California. Each donor underwent a thorough consent process – including being shown a detailed brochure – to explain what iPS cells are and how the research would be done.
The diseases to be studied through this bank include:
Age-Related Macular Degeneration (AMD)
Alzheimer’s disease
Autism Spectrum Disorder (ASD)
Cardiomyopathies (heart conditions)
Cerebral Palsy
Diabetic Retinopathy
Epilepsy
Fatty Liver diseases
Hepatitis C (HCV)
Intellectual Disabilities
Primary Open Angle Glaucoma
Pulmonary Fibrosis
The samples were screened to make sure they were safe – for example the blood was tested for HBV and HIV – and then underwent rigorous quality control testing to make sure they met the highest standards.
Once approved the samples were then turned into iPSCs at a special facility at the Buck Institute in Novato and those lines were then made available to researchers around the world, both for-profit and non-profit entities.
Scientists are now able to use these cells for a wide variety of uses including disease modeling, drug discovery, drug development, and transplant studies in animal research models. It gives them a greater ability to study how a disease develops and progresses and to help discover and test new drugs or other therapies
The Bank, which is now run by FUJIFILM Cellular Dynamics, has become a powerful resource for studying genetic variation between individuals, helping scientists understand how disease and treatment vary in a diverse population. Both CIRM and Fuji Film are committed to making even more improvements and additions to the collection in the future to ensure this is a vital resource for researchers for years to come.
Do an online search for “autism stem cells” and you quickly come up with numerous websites offering stem cell therapies for autism. They offer encouraging phrases like “new and effective approach” and “a real, lasting treatment.” They even include dense scientific videos featuring people like Dr. Arnold Caplan, a professor at Case Western Reserve University who is known as the “father of the mesenchymal stem” (it would be interesting to know if Dr. Caplan knows he is being used as a marketing tool?)
The problem with these sites is that they are offering “therapies” that have never been proven to be safe, let alone effective. They are also very expensive and are not covered by insurance. Essentially they are preying on hope, the hope that any parent of a child with autism spectrum disorder (ASD) will do anything and everything they can to help their child.
But there is encouraging news about stem cells and autism, about their genuine potential to help children with ASD. That’s why we are holding a special Facebook Live “Ask the Stem Cell Team” about Autism on Thursday, March 19th at noon (PDT).
The event features Dr. Alysson Muotri from UC San Diego. We have written about his work with stem cells for autism in the past. And CIRM’s own Associate Director for Discovery and Translation, Dr. Kelly Shephard.
We’ll take a look at Dr. Muotri’s work and also discuss the work of other researchers in the field, such as Dr. Joanne Kurtzberg’s work at Duke University.
But we also want you to be a part of this as well. So, join us online for the event. You can post comments and questions during the event, and we’ll do our best to answer them. Or you can send us in questions ahead of time to info@cirm.ca.gov.
Dr. Bennett Novitch, UCLA Broad Stem Cell Research Center Image Credit: UCLA Broad Stem Cell Research Center
In a previous blog post, we discussed new findings in a CIRM supported study at the Salk Institute for Autism Spectrum Disorder (ASD), a developmental disorder that comes in broad ranges and primarily affects communication and behavior.
This week, a new study, also supported by CIRM, finds that a gene associated with ASD, intellectual disability, and language impairment can affect brain stem cells, which in turn, influence early brain development. Dr. Bennett Novitch and his team at UCLA evaluated a gene, called Foxp1, which has been previously studied for its function in the neurons in the developing brain.
Image showing brain cells with lower levels of Foxp1 function (left) and higher levels (right). neural stem cells are stained in green; secondary progenitors and neurons in red. Image Credit: UCLA Broad Stem Cell Research Center
In this study, Dr. Novitch and his team looked at Foxp1 levels in the brains of developing mouse embryos. What they discovered is that, in normal developing mice the gene was active much earlier than previous studies had indicated. It turns out that the gene was active during the period when neural stem cells are just beginning to expand in numbers and generate a subset of brain cells found deep within the developing brain.
When mice lacked the gene entirely, there were fewer neural stem cells at early stages of brain development, as well as fewer brain cells deep within the developing brain. Alternatively, when the levels of the gene were above normal, the researchers found significantly more neural stem cells and brain cells deep within the developing brain. Additionally, higher levels of the neural stem cells were observed in mice with high levels of the gene even after they were born.
In a press release from UCLA, Dr. Novitch explains how the different levels of the gene can be tied to the variation of Foxp1 levels seen in ASD patients.
“What we saw was that both too much and too little Foxp1 affects the ability of neural stem cells to replicate and form certain neurons in a specific sequence in mice. And this fits with the structural and behavioral abnormalities that have been seen in human patients.”
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.
I had an Ischemic stroke in 2014, and my vision was also affected. Can stem cells possibly help with my vision issues. James Russell
Dr. Lila Collins:
Hi James. Vision loss from stroke is complex and the type of loss depends upon where the stroke occurred (in the actual eye, the optic nerve or to the other parts of the brain controlling they eye or interpreting vision). The results could be:
Visual loss from damage to the retina
You could have a normal eye with damage to the area of the brain that controls the eye’s movement
You could have damage to the part of the brain that interprets vision.
You can see that to address these various issues, we’d need different cell replacement approaches to repair the retina or the parts of the brain that were damaged.
Replacing lost neurons is an active effort that at the moment is still in the research stages. As you can imagine, this is complex because the neurons have to make just the right connections to be useful.
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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?
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.
Fragile X syndrome (FXS) is a genetic disorder that is the most common form of inherited intellectual disability in children, and has also been linked to a form of autism. Uncovering the cause of FXS could help lead to a deeper understanding of autism, what causes it and ultimately, it’s hoped, to treating or even preventing it.
Researchers at Children’s Hospital in Chicago looked at FXS at the stem cell level and found how a genetic defect has an impact on the development of neurons (nerve cells in the brain) and how that in turn has an impact on the developing brain in the fetus.
In a news release on Eurekalert, Dr. Yongchao Ma, the senior author of the study, says this identified a problem at a critical point in the development of the brain:
“During embryonic brain development,
the right neurons have to be produced at the right time and in the right
numbers. We focused on what happens in the stem cells that leads to slower
production of neurons that are responsible for brain functions including learning
and memory. Our discoveries shed light on the earliest stages of disease
development and offer novel targets for potential treatments.”
The team looked at neural stem cells and found that a lack
of one protein, called FMRP, created a kind of cascade that impacted the
ability of the cells to turn into neurons. Fewer neurons meant impaired brain
development.
The findings, published in the journal Cell Reports, help explain how
genetic information flows in cells in developing babies and, according to Dr.
Ma, could lead to new ideas on how to treat problems.
“Currently we are exploring how to
stimulate FMRP protein activity in the stem cell, in order to correct the
timing of neuron production and ensure that the correct amount and types of
neurons are available to the developing brain. There may be potential for gene
therapy for fragile X syndrome.”
Cave paintings from Libya: evidence humans communicated through visual images long before they created text
There’s a large body of research that shows that many people learn better through visuals. Studies show that much of the sensory cortex in our brain is devoted to vision so our brains use images rather than text to make sense of things.
That’s why we think it just makes sense to use visuals, as much as we can, when trying to help people understand advances in stem cell research. That’s precisely what our colleagues at U.C. San Diego are doing with a new show called “Stem Cell Science with Alysson Muotri”.
Alysson is a CIRM grantee
who is doing some exciting work in developing a deeper understanding of autism.
He’s also a really good communicator who can distill complex ideas down into
easy to understand language.
The show features Alysson,
plus other scientists at UCSD who are working hard to move the most promising
research out of the lab and into clinical trials in people. Appropriately the
first show in the series follows that path, exploring
how discoveries made using tiny Zebrafish could hopefully lead to stem cell
therapies targeting blood diseases like leukemia. This first show also highlights
the important role that CIRM’s Alpha Stem Cell Clinic Network will play in
bringing those therapies to patients.
You can find a sneak preview of the show on YouTube. The series proper will be broadcast on California local cable via the UCTV channel at 8:00 pm on Thursdays starting July 8, 2019.
And if you really
have a lot of time on your hands you can check out the more
than 300 videos CIRM has produced on every aspect of stem cell research
from cures for fatal diseases to questions to ask before taking part in a
clinical trial.
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.
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.
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.
Congresswoman Barbara Lee (D-CA 13th District)
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 Stem Cellar’s Image of the Week. Our favorite image this week, comes to us from researchers at Washington University School of Medicine in St. Louis. Looking like a psychedelic Rorschach test, the fluorescence microscopy depicts mouse olfactory epithelium (in green), a sheet of tissue that develops in the nose. The team identified a new stem cell type that controls the growth of this tissue. New insights from the study of these cells could help the team better understand why some animals, like dogs, have a far superior sense of smell than humans.
Peering into the nasal cavity of a mouse. Olfactory epithelium is indicated by green. Image credit: Lu Yang, Washington University School of Medicine in St. Louis.
How stress affects blood-forming stem cells. Stress affects all of us in different ways. Some people handle it well. Some crack up and become nervous wrecks. So, perhaps it shouldn’t come as a huge surprise that stress also affects some stem cells. What is a pleasant surprise is that knowing this could help people undergoing cancer therapy or bone marrow transplants.
First a bit of background. Hematopoietic, or blood-forming stem cells (HSCs) come from bone marrow and are supported by other cells that secrete growth factors, including one called pleiotrophin or PTN. While researchers knew PTN was present in bone marrow they weren’t sure precisely what role it played.
So, researchers at UCLA set out to discover what PTN did.
In a CIRM-funded study they took mice that lacked PTN in endothelial cells – these line the blood vessels – or in their stromal cells – which make up the connective tissue. They found that a lack of PTN in stromal cells caused a lack of blood stem cells, but a lack of PTN in endothelial cells had no impact.
Expression of pleiotrophin (green) in bone marrow blood vessels (red) and stromal cells (white) is shown in normal mice (left) and in mice at 24 hours following irradiation (right). Image credit: UCLA
However, as Dr. John Chute explained in a news release, when they stressed the cells, by exposing them to radiation, they found something very different:
“The surprising finding was that pleiotrophin from stromal cells was not necessary for blood stem cell regeneration following irradiation — but pleiotrophin from endothelial cells was necessary.”
In other words, during normal times the stem cells rely on PTN from stromal cells, but after stress they depend on PTN from endothelial cells.
Dr. Chute says, because treatments like chemotherapy and radiation deplete bone marrow stem cells, this finding could have real-world implications for patients.
“These therapies for cancer patients suppress our blood cell systems over time. It may be possible to administer modified, recombinant versions of pleiotrophin to patients to accelerate blood cell regeneration. This strategy also may apply to patients undergoing bone marrow transplants.”
Predicting the fate of cells with math Researchers at Harvard Medical School and the Karolinska Institutet in Sweden reported this week that they have devised a mathematical model that can predict the fate of stem cells in the brain.
It may sound like science-fiction but the accomplished the feat by tracking changes in messenger RNA (mRNA), the genetic molecule that translates our DNA code into instructions for building proteins. As a brain stem cell begins specializing into specific cell types, hundreds of genes get turns on and off, which is observed by the rate of changes in mRNA productions.
The team built their predictive model by measuring these changes. In a press release, co-senior author, Harvard professor Peter Kharchenko, described this process using a great analogy:
“Estimating RNA velocity—or the rate of RNA change over time—is akin to observing the cooks in a restaurant kitchen as they line up the ingredients to figure out what dishes they’ll be serving up next.”
The team verified their mathematical model by inputting other data that was not use in constructing the model. Karolinkska Institutet professor, Sten Linnarsson, the other co-senior author on the study, described how such a model could be applied to human biomedical research:
“RNA velocity shows in detail how neurons and other cells acquire their specific functions as the brain develops and matures. We’re especially excited that this new method promises to help reveal how brains normally develop, but also to provide clues as to what goes wrong in human disorders of brain development, such as schizophrenia and autism.”
Stanford lab develops method to make nerve cells from blood.
Induced neuronal (iN) cells derived from adult human blood cells. Credit: Marius Wernig, Stanford University.
Back in 2010, Stanford Professor Marius Wernig and his team devised a method to directly convert skin cells into neurons, a nerve cell. This so-called transdifferentiation technique leapfrogs over the need to first reprogram the skin cells into induced pluripotent stem cells. This breakthrough provided a more efficient path to studying how genetics plays a role in various mental disorders, like autism or schizophrenia, using patient-derived cells. But these types of genetic analyses require data from many patients and obtaining patient skin samples hampered progress because it’s not only an invasive, somewhat painful procedure but it also takes time and money to prepare the tissue sample for the transdifferentiation method.
This week, the Wernig lab reported on a solution to this bottleneck in the journal, PNAS. The study, funded in part by CIRM, describes a variation on their transdifferentiation method which converts T cells from the immune system, instead of skin cells, into neurons. The huge advantage with T cells is that they can be isolated from readily available blood samples, both fresh or frozen. In a press release, Wernig explains this unexpected but very welcomed result:
“It’s kind of shocking how simple it is to convert T cells into functional neurons in just a few days. T cells are very specialized immune cells with a simple round shape, so the rapid transformation is somewhat mind-boggling. We now have a way to directly study the neuronal function of, in principle, hundreds of people with schizophrenia and autism. For decades we’ve had very few clues about the origins of these disorders or how to treat them. Now we can start to answer so many questions.”
Two studies targeting Parkinson’s offer new clues to treating the disease (Kevin McCormack) Despite decades of study, Parkinson’s disease remains something of a mystery. We know many of the symptoms – trembling hands and legs, stiff muscles – are triggered by the loss of dopamine producing cells in the brain, but we are not sure what causes those cells to die. Despite that lack of certainty researchers in Germany may have found a way to treat the disease.
Simple diagram of a mitochondria.
They took skin cells from people with Parkinson’s and turned them into the kinds of nerve cell destroyed by the disease. They found the cells had defective mitochondria, which help produce energy for the cells. Then they added a form of vitamin B3, called nicotinamide, which helped create new, healthy mitochondria.
In an article in Science & Technology Research News Dr. Michela Deleidi, the lead researcher on the team, said this could offer new pathways to treat Parkinson’s:
“This substance stimulates the faulty energy metabolism in the affected nerve cells and protects them from dying off. Our results suggest that the loss of mitochondria does indeed play a significant role in the genesis of Parkinson’s disease. Administering nicotinamide riboside may be a new starting-point for treatment.”
The study is published in the journal Cell Reports.
While movement disorders are a well-recognized feature of Parkinson’s another problem people with the condition suffer is sleep disturbances. Many people with Parkinson’s have trouble falling asleep or remaining asleep resulting in insomnia and daytime sleepiness. Now researchers in Belgium may have uncovered the cause.
Working with fruit flies that had been genetically modified to have Parkinson’s symptoms, the researchers discovered problems with neuropeptidergic neurons, the type of brain cell that helps regulate sleep patterns. Those cells seemed to lack a lipid, a fat-like substance, called phosphatidylserine.
In a news release Jorge Valadas, one of the lead researchers, said replacing the missing lipid produced promising results:
“When we model Parkinson’s disease in fruit flies, we find that they have fragmented sleep patterns and difficulties in knowing when to go to sleep or when to wake up. But when we feed them phosphatidylserine–the lipid that is depleted in the neuropeptidergic neurons–we see an improvement in a matter of days.”
Next, the team wants to see if the same lipids are low in people with Parkinson’s and if they are, look into phosphatidylserine – which is already approved in supplement form – as a means to help ease sleep problems.
With patient-derived induced pluripotent stem cells (iPSCs) in hand, any lab scientist can follow recipes that convert these embryonic-like stem cells into specific cell types for studying human disease in a petri dish. iPSCs derived from a small skin sample from a Alzheimer’s patient, for instance, can be specialized into neurons – the kind of cell affected by the disease – to examine what goes wrong in an Alzheimer’s patient’s brain or screen drugs that may alleviate the problems.
Neurons created from Alzheimer’s disease patient-derived iPSCs. Image courtesy Elixirgen Scientific
But not every researcher has easy access to a bank of patient-derived iPSCs and it’s not trivial to coax iPSCs to become a particular cell type. The process is also a time sink and many scientists would rather spend that time doing what they’re good at: uncovering new insights into their disease of interest.
Since the discovery of iPSC technology over a decade ago, countless labs have worked out increasingly efficient variations on the original method. In fact, companies that deliver iPSC-derived products have emerged as an attractive option for the time-strapped stem cell researcher.
One of those companies is Elixirgen Scientific of Baltimore, Maryland. Pardon the pun but Elixirgen has turned the process of making various cell types from iPSCs into a science. Here’s how CEO Bumpei Noda described the company’s value to me:
Bumpei Noda
“Our technology directly changes stem cells into the cells that make up most of your body, such as muscle cells or neural cells, in about one week. Considering that existing technology takes multiple weeks or even months to do the same thing, imagine how much more research can get done than before.”
With Elixirgen’s technology, different “cocktails” of ingredients can quickly and efficiently turn iPSCs into many different human cell types. Image courtesy Elixirgen Scientific
Their technology is set to become an even greater resource for researchers based on their announcement yesterday that they’ve signed a licensing agreement to sell human disease cells that were generated from CIRM’s iPSC Repository.
Stephen Lin
“The CIRM Repository holds the largest publicly accessible collection of human iPSCs in the world and is the result of years of coordinated efforts of many groups to create a leading resource for disease modeling and drug discovery using stem cells,” said Stephen Lin, a CIRM Senior Science Officer who oversees the cell bank.
The repository currently contains a collection of 1,600 cell lines derived from patients with diseases that are a source of active research, including autism, epilepsy, cerebral palsy, Alzheimer’s disease, heart disease, lung disease, hepatitis C, fatty liver disease, and more (visit our iPSC Repository web page for the complete list).
While this wide variety of patient cells lines certainly played a major role in Elixirgen’s efforts to sign the agreement, Noda also noted that the CIRM Repository “has rich clinical and demographic data and age-matched control cell lines” which is key information to have when interpreting the results of experiments and drug screening.
Lin also points out another advantage to the CIRM cells:
“It’s one of the few collections with a streamlined route to commercialization (i.e. pre-negotiated licenses) that make activities like Elixirgen’s possible. iPSC technology is still under patent and technically cannot be used for drug discovery without those legal safeguards. That’s important because if you do discover a drug using iPSCs without taking care of these licensing agreements, your discovery could be owned by that original intellectual property holder.”
At CIRM, we’re laser-focused on accelerating stem cell treatments to patients with unmet medical needs. That’s why we’re excited that Elixirgen Scientific has licensed access to the our iPSC repository. We’re confident their service will help researchers work more efficiently and, in turn, accelerate the pace of new discoveries.
The Stem Cellar 