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.
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)
Autism Spectrum Disorder (ASD)
Cardiomyopathies (heart conditions)
Fatty Liver diseases
Hepatitis C (HCV)
Primary Open Angle Glaucoma
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.
We are at a turning point in regenerative medicine as the first wave of treatments have obtained FDA approval. But at the same time as we see the advance of scientifically rigorous research and regulated products we are also witnessing the continued proliferation of “unproven treatments.” This dueling environment can be overwhelming and distracting to individuals and families trying to manage life-threatening diseases.
How does a patient navigate this environment and get trusted and reliable information to help sort through their options?
CIRM teamed up with the CURA Foundation to organize a roundtable discussion intended to answer this question. The conversation included thought leaders involved in patient advocacy, therapy research and development, public policy and research funding. The roundtable was divided into three segments designed to discuss:
Examples of state-of-the-art patient navigation systems,
Policy, research and infrastructure needs required to expand navigation systems, and
Communication needs for engaging patients and the broader community.
Examples of Navigation Systems:
This session was framed around the observation that patients often do not get the best medicines or treatments available for their condition. For example, in the area of cancer care there is evidence that the top 25% of cancers are not being treated optimally. Historic barriers to optimal treatment include cost pressures that may block access to treatments, lack of knowledge about the available treatments or the absence of experts in the location where the patient is being treated. Much of the session focused on how these barriers are being overcome by partnerships between health care provides, employers and patients.
For example, new technologies such as DNA sequencing and other cell-based markers enable better diagnosis of a patient’s underlying disease. This information can be collected by a community hospital and shared with experts who work with the treating doctor to consider the best options for the patient. If patients need to access a specialty center for treatment, there are new models for the delivery of such care. Emphasis is placed on building a relationship with the patient and their family by surrounding them with a team that can address any questions that arise. The model of patient-centered care is being embraced by employers who are purchasing suites of services for their employees.
Patient advocacy groups have also supported efforts to get the best information about the patients’ underlying disease. Advocacy organizations have been building tools to connect patients with researchers with the aim of allowing secure and responsible sharing of medical information to drive the patient-centered development of new treatments. In a related initiative, the American Society of Hematology is creating a data hub for clinical trials for sickle cell disease. Collectively, these efforts are designed to accelerate new treatments by allowing critical data to be shared among researchers.
Essential Policy Infrastructure for Regenerative Medicine:
Session two dovetailed nicely with first discussion. There was continued emphasis on the need for additional evidence (data) to demonstrate that regenerative medicine treatments are having a significant effect on the patient’s disease. Various speakers echoed the need for patients in clinical trials to work with researchers to determine the benefits of treatments. Success stories with gene therapies in blood diseases were cited as proof of concept where treatments being evaluated in clinical trials are demonstrating a significant and sustained impact on diseases. Evidence of benefit is needed by both regulatory bodies that approve the treatments, such as the FDA, and by public and private payers / insurers that pay for treatments and patients that need to know the best option for their particular disease.
In addition, various speakers cited the continued proliferation of “unproven treatments” being marketed by for-profit centers. There was broad concern that the promotion of treatment where there is no evidence of effectiveness will mislead some patients and potentially harm the scientifically rigorous development of new treatments. Particularly for “stem cell” treatments, there was a desire to develop evaluation criteria that are clear and transparent to allow legitimate treatments to be distinguished from those with no evidence of effectiveness. One participant suggested there be a scorecard approach where specific treatments could be rated against specific indicators of safety, medical benefit and value in relation to alternative treatments. The idea would be to make this information widely available to patients, medical providers and the public to inform everything from medical decision making to advertising.
Communicating the Vision
The final session considered communication needs for the field of regenerative medicine. Patients and patient advocacy organizations described how they are using social media and other networking tools to share information and experiences in navigating their treatment options. Patient advocacy groups also described the challenges from providers of unproven treatments. In one case, a for profit “pop up” clinic had used the group’s videos in an attempt to legitimize their unproven treatment.
There was general consensus among the panelists that the field of regenerative medicine needs “trusted intermediaries” who can evaluate claims and help patients distinguish between high quality research and “snake oil”. These intermediaries should have the capacity to compile the most reliable evidence and utilize it to determine what options are available to patients. In addition, there needs to be shared decision making model where patients have the opportunity to explore options in an unbiased environment so they may make the best decision based on their specific needs and values.
Creating this kind of Navigation System will not be easy but the alternative is unacceptable. Too many vulnerable patients are being taken advantage of by the growing number of “predatory clinics” hawking expensive therapies that are both unproven and unapproved. We owe it to these patients to create a simple way for them to identify what are the most promising therapies, ones that have the highest chance of being both safe and effective. The roundtable discussion marked a starting point, bringing together many of the key players in the field, highlighting the key issues and beginning to identify possible solutions.
On December 12th we hosted our latest ‘Facebook Live: Ask the Stem Cell Team’ event. This time around we really did mean team. We had a host of our Science Officers answering questions from friends and supporters of CIRM. We got a lot of questions and didn’t have enough time to address them all. So here’s answers to all the questions.
What are the obstacles to using partial cellular reprogramming to return people’s entire bodies to a youthful state.Paul Hartman. San Leandro, California
Dr. Kelly Shepard: Certainly, scientists have observed that various manipulations of cells, including reprogramming, partial reprogramming, de-differentiation and trans-differentiation, can restore or change properties of cells, and in some cases, these changes can reflect a more “youthful” state, such as having longer telomeres, better proliferative capacity, etc. However, some of these same rejuvenating properties, outside of their normal context, could be harmful or deadly, for example if a cell began to grow and divide when or where it shouldn’t, similar to cancer. For this reason, I believe the biggest obstacles to making this approach a reality are twofold: 1) our current, limited understanding of the nature of partially reprogrammed cells; and 2) our inability to control the fate of those cells that have been partially reprogrammed, especially if they are inside a living organism. Despite the challenges, I think there will be step wise advances where these types of approaches will be applied, starting with specific tissues. For example, CIRM has recently funded an approach that uses reprogramming to make “rejuvenated” versions of T cells for fighting lung cancer. There is also a lot of interest in using such approaches to restore the reparative capacity of aged muscle. Perhaps some successes in these more limited areas will be the basis for expanding to a broader use.
What’s going on with Stanford’s stem cell trials for stroke? I remember the first trial went really well In 2016 have not heard anything about since? Elvis Arnold
Dr. Lila Collins: Hi Elvis, this is an evolving story. I believe you are referring to SanBio’s phase 1/2a stroke trial, for which Stanford was a site. This trial looked at the safety and feasibility of SanBio’s donor or allogeneic stem cell product in chronic stroke patients who still had motor deficits from their strokes, even after completing physical therapy when natural recovery has stabilized. As you note, some of the treated subjects had promising motor recoveries.
SanBio has since completed a larger, randomized phase 2b trial in stroke, and they have released the high-level results in a press release. While the trial did not meet its primary endpoint of improving motor deficits in chronic stroke, SanBio conducted a very similar randomized trial in patients with stable motor deficits from chronic traumatic brain injury (TBI). In this trial, SanBio saw positive results on motor recovery with their product. In fact, this product is planned to move towards a conditional approval in Japan and has achieved expedited regulatory status in the US, termed RMAT, in TBI which means it could be available more quickly to patients if all goes well. SanBio plans to continue to investigate their product in stroke, so I would stay tuned as the work unfolds.
Also, since you mentioned Stanford, I should note that Dr Gary Steinberg, who was a clinical investigator in the SanBio trial you mentioned, will soon be conducting a trial with a different product that he is developing, neural progenitor cells, in chronic stroke. The therapy looks promising in preclinical models and we are hopeful it will perform well for patients in the clinic.
I am a stroke survivor will stem cell treatment able to restore my motor skills?Ruperto
Dr. Lila Collins:
Hi Ruperto. Restoring motor loss after stroke is a very active area of research. I’ll touch upon a few ongoing stem cell trials. I’d just like to please advise that you watch my colleague’s comments on stem cell clinics (these can be found towards the end of the blog) to be sure that any clinical research in which you participate is as safe as possible and regulated by FDA.
Back to stroke, I mentioned SanBio’s ongoing work to address motor skill loss in chronic stroke earlier. UK based Reneuron is also conducting a phase 2 trial, using a neural progenitor cell as a candidate therapy to help recover persistent motor disability after stroke (chronic). Dr Gary Steinberg at Stanford is also planning to conduct a clinical trial of a human embryonic stem cell-derived neuronal progenitor cell in stroke.
There is also promising work being sponsored by Athersys in acute stroke. Athersys published results from their randomized, double blinded placebo controlled Ph2 trial of their Multistem product in patients who had suffered a stroke within 24-48 hours. After intravenous delivery, the cells improved a composite measure of stroke recovery, including motor recovery. Rather than acting directly on the brain, Multistem seems to work by traveling to the spleen and reducing the inflammatory response to a stroke that can make the injury worse.
Athersys is currently recruiting a phase 3 trial of its Multistem product in acute stroke (within 1.5 days of the stroke). The trial has an accelerated FDA designation, called RMAT and a special protocol assessment. This means that if the trial is conducted as planned and it reaches the results agreed to with the FDA, the therapy could be cleared for marketing. Results from this trial should be available in about two years.
Questions from several hemorrhagic stroke survivors who say most clinical trials are for people with ischemic strokes. Could stem cells help hemorrhagic stroke patients as well?
Dr. Lila Collins:
Regarding hemorrhagic stroke, you are correct the bulk of cell therapies for stroke target ischemic stroke, perhaps because this accounts for the vast bulk of strokes, about 85%.
That said, hemorrhagic strokes are not rare and tend to be more deadly. These strokes are caused by bleeding into or around the brain which damages neurons. They can even increase pressure in the skull causing further damage. Because of this the immediate steps treating these strokes are aimed at addressing the initial bleeding insult and the blood in the brain.
While most therapies in development target ischemic stroke, successful therapies developed to repair neuronal damage or even some day replace lost neurons, could be beneficial after hemorrhagic stroke as well.
I had an Ischemic stroke in 2014, and my vision was also affected. Can stem cells possibly help with my vision issues. James Russell
Dr. Lila Collins:
Hi James. Vision loss from stroke is complex and the type of loss depends upon where the stroke occurred (in the actual eye, the optic nerve or to the other parts of the brain controlling they eye or interpreting vision). The results could be:
Visual loss from damage to the retina
You could have a normal eye with damage to the area of the brain that controls the eye’s movement
You could have damage to the part of the brain that interprets vision.
You can see that to address these various issues, we’d need different cell replacement approaches to repair the retina or the parts of the brain that were damaged.
Replacing lost neurons is an active effort that at the moment is still in the research stages. As you can imagine, this is complex because the neurons have to make just the right connections to be useful.
Is there any stem cell therapy for optical nerve damage? Deanna Rice
Dr. Ingrid Caras: There is currently no proven stem cell therapy to treat optical nerve damage, even though there are shady stem cell clinics offering treatments. However, there are some encouraging early gene therapy studies in mice using a virus called AAV to deliver growth factors that trigger regeneration of the damaged nerve. These studies suggest that it may be possible to restore at least some visual function in people blinded by optic nerve damage from glaucoma
I read an article about ReNeuron’s retinitis pigmentosa clinical trial update. In the article, it states: “The company’s treatment is a subretinal injection of human retinal progenitors — cells which have almost fully developed into photoreceptors, the light-sensing retinal cells that make vision possible.” My question is: If they can inject hRPC, why not fully developed photoreceptors?Leonard
Dr. Kelly Shepard: There is evidence from other studies, including from other tissue types such as blood, pancreas, heart and liver, that fully developed (mature) cell types tend not to engraft as well upon transplantation, that is the cells do not establish themselves and survive long term in their new environment. In contrast, it has been observed that cells in a slightly less “mature” state, such as those in the progenitor stage, are much more likely to establish themselves in a tissue, and then differentiate into more mature cell types over time. This question gets at the crux of a key issue for many new therapies, i.e. what is the best cell type to use, and the best timing to use it.
My question for the “Ask the Stem Cell Team” event is: When will jCyte publish their Phase IIb clinical trial results. Chris Allen
Dr. Ingrid Caras: The results will be available sometime in 2020.
I understand the hRPC cells are primarily neurotropic (rescue/halt cell death); however, the literature also says hRPC can become new photoreceptors. My questions are:Approximately what percentage develop into functioning photoreceptors? And what percentage of the injected hRPC are currently surviving?Leonard Furber, an RP Patient
Dr. Kelly Shepard: While we can address these questions in the lab and in animal models, until there is a clinical trial, it is not possible to truly recreate the environment and stresses that the cells will undergo once they are transplanted into a human, into the site where they are expected to survive and function. Thus, the true answer to this question may not be known until after clinical trials are performed and the results can be evaluated. Even then, it is not always possible to monitor the fate of cells after transplantation without removing tissues to analyze (which may not be feasible), or without being able to transplant labeled cells that can be readily traced.
Dr. Ingrid Caras – Although the cells have been shown to be capable of developing into photoreceptors, we don’t know if this actually happens when the cells are injected into a patient’s eye. The data so far suggest that the cells work predominantly by secreting growth factors that rescue damaged retinal cells or even reverse the damage. So one possible outcome is that the cells slow or prevent further deterioration of vision. But an additional possibility is that damaged retinal cells that are still alive but are not functioning properly may become healthy and functional again which could result in an improvement in vision.
What advances have been made using stem cells for the treatment of Type 2 Diabetes?Mary Rizzo
Dr. Ross Okamura: Type 2 Diabetes (T2D) is a disease where the body is unable to maintain normal glucose levels due to either resistance to insulin-regulated control of blood sugar or insufficient insulin production from pancreatic beta cells. The onset of disease has been associated with lifestyle influenced factors including body mass, stress, sleep apnea and physical activity, but it also appears to have a genetic component based upon its higher prevalence in certain populations.
Type 1 Diabetes (T1D) differs from T2D in that in T1D patients the pancreatic beta cells have been destroyed by the body’s immune system and the requirement for insulin therapy is absolute upon disease onset rather than gradually developing over time as in many T2D cases. Currently the only curative approach to alleviate the heavy burden of disease management in T1D has been donor pancreas or islet transplantation. However, the supply of donor tissue is small relative to the number of diabetic patients. Donor islet and pancreas transplants also require immune suppressive drugs to prevent allogenic immune rejection and the use of these drugs carry additional health concerns. However, for some patients with T1D, especially those who may develop potentially fatal hypoglycemia, immune suppression is worth the risk.
To address the issue of supply, there has been significant activity in stem cell research to produce insulin secreting beta cells from pluripotent stem cells and recent clinical data from Viacyte’s CIRM funded trial indicates that implanted allogeneic human stem cell derived cells in T1D patients can produce circulating c-peptide, a biomarker for insulin. While the trial is not designed specifically to cure insulin-dependent T2D patients, the ability to produce and successfully engraft stem cell-derived beta cells would be able to help all insulin-dependent diabetic patients.
It’s also worth noting that there is a sound scientific reason to clinically test a patient-derived pluripotent stem cell-based insulin-producing cells in insulin-dependent T2D diabetic patients; the cells in this case could be evaluated for their ability to cure diabetes in the absence of needing to prevent both allogeneic and autoimmune responses.
SPINAL CORD INJURY
Is there any news on clinical trials for spinal cord injury? Le Ly
Kevin McCormack: The clinical trial CIRM was funding, with Asterias (now part of a bigger company called Lineage Cell Therapeutics, is now completed and the results were quite encouraging. In a news release from November of 2019 Brian Culley, CEO of Lineage Cell Therapeutics, described the results this way.
“We remain extremely excited about the potential for OPC1 (the name of the therapy used) to provide enhanced motor recovery to patients with spinal cord injuries. We are not aware of any other investigative therapy for SCI (spinal cord injury) which has reported as encouraging clinical outcomes as OPC1, particularly with continued improvement beyond 1 year. Overall gains in motor function for the population assessed to date have continued, with Year 2 assessments measuring the same or higher than at Year 1. For example, 5 out of 6 Cohort 2 patients have recovered two or more motor levels on at least one side as of their Year 2 visit whereas 4 of 6 patients in this group had recovered two motor levels as of their Year 1 visit. To put these improvements into perspective, a one motor level gain means the ability to move one’s arm, which contributes to the ability to feed and clothe oneself or lift and transfer oneself from a wheelchair. These are tremendously meaningful improvements to quality of life and independence. Just as importantly, the overall safety of OPC1 has remained excellent and has been maintained 2 years following administration, as measured by MRI’s in patients who have had their Year 2 follow-up visits to date. We look forward to providing further updates on clinical data from SCiStar as patients continue to come in for their scheduled follow up visits.”
Lineage Cell Therapeutics plans to meet with the FDA in 2020 to discuss possible next steps for this therapy.
In the meantime the only other clinical trial I know that is still recruiting is one run by a company called Neuralstem. Here is a link to information about that trial on the www.clinicaltrials.gov website.
Now that the Brainstorm ALS trial is finished looking for new patients do you have any idea how it’s going and when can we expect to see results? Angela Harrison Johnson
Dr. Ingrid Caras: The treated patients have to be followed for a period of time to assess how the therapy is working and then the data will need to be analyzed. So we will not expect to see the results probably for another year or two.
Are there treatments for autism or fragile x using stem cells? Magda Sedarous
Dr. Kelly Shepard: Autism and disorders on the autism spectrum represent a collection of many different disorders that share some common features, yet have different causes and manifestations, much of which we still do not understand. Knowing the origin of a disorder and how it affects cells and systems is the first step to developing new therapies. CIRM held a workshop on Autism in 2009 to brainstorm potential ways that stem cell research could have an impact. A major recommendation was to exploit stem cells and new technological advances to create cells and tissues, such as neurons, in the lab from autistic individuals that could then be studied in great detail. CIRM followed this recommendation and funded several early-stage awards to investigate the basis of autism, including Rett Syndrome, Fragile X, Timothy Syndrome, and other spectrum disorders. While these newer investigations have not yet led to therapies that can be tested in humans, this remains an active area of investigation. Outside of CIRM funding, we are aware of more mature studies exploring the effects of umbilical cord blood or other specific stem cell types in treating autism, such as an ongoing clinical trial conducted at Duke University.
What is happening with Parkinson’s research? Hanifa Gaphoor
Dr. Kent Fitzgerald: Parkinson’s disease certainly has a significant amount of ongoing work in the regenerative medicine and stem cell research.
The nature of cell loss in the brain, specifically the dopaminergic cells responsible for regulating the movement, has long been considered a good candidate for cell replacement therapy.
This is largely due to the hypothesis that restoring function to these cells would reverse Parkinson’s symptoms. This makes a lot of sense as front line therapy for the disease for many years has been dopamine replacement through L-dopa pills etc. Unfortunately, over time replacing dopamine through a pill loses its benefit, whereas replacing or fixing the cells themselves should be a more permanent fix.
Because a specific population of cells in one part of the brain are lost in the disease, multiple labs and clinicians have sought to replace or augment these cells by transplantation of “new” functional cells able to restore function to the area an theoretically restore voluntary motor control to patients with Parkinson’s disease.
Early clinical research showed some promise, however also yielded mixed results, using fetal tissue transplanted into the brains of Parkinson’s patients. As it turns out, the cell types required to restore movement and avoid side effects are somewhat nuanced. The field has moved away from fetal tissue and is currently pursuing the use of multiple stem cell types that are driven to what is believed to be the correct subtype of cell to repopulate the lost cells in the patient.
One project CIRM sponsored in this area with Jeanne Loring sought to develop a cell replacement therapy using stem cells from the patients themselves that have been reprogrammed into the kinds of cell damaged by Parkinson’s. This type of approach may ultimately avoid issues with the cells avoiding rejection by the immune system as can be seen with other types of transplants (i.e. liver, kidney, heart etc).
Still, others are using cutting edge gene therapy technology, like the clinical phase project CIRM is sponsoring with Krystof Bankiewicz to investigate the delivery of a gene (GDNF) to the brain that may help to restore the activity of neurons in the Parkinson’s brain that are no longer working as they should.
The bulk of the work in the field of PD at the present remains centered on replacing or restoring the dopamine producing population of cells in the brain that are affected in disease.
Any plans for Huntington’s?Nikhat Kuchiki
Dr. Lisa Kadyk: The good news is that there are now several new therapeutic approaches to Huntington’s Disease that are at various stages of preclinical and clinical development, including some that are CIRM funded. One CIRM-funded program led by Dr. Leslie Thompson at UC Irvine is developing a cell-based therapeutic that consists of neural stem cells that have been manufactured from embryonic stem cells. When these cells are injected into the brain of a mouse that has a Huntington’s Disease mutation, the cells engraft and begin to differentiate into new neurons. Improvements are seen in the behavioral and electrophysiological deficits in these mutant mice, suggesting that similar improvements might be seen in people with the disease. Currently, CIRM is funding Dr. Thompson and her team to carry out rigorous safety studies in animals using these cells, in preparation for submitting an application to the FDA to test the therapy in human patients in a clinical trial.
There are other, non-cell-based therapies also being tested in clinical trials now, using anti-sense oligonucleotides (Ionis, Takeda) to lower the expression of the Huntington protein. Another HTT-lowering approach is similar – but uses miRNAs to lower HTT levels (UniQure,Voyager)
TRAUMATIC BRAIN INJURY (TBI)
My 2.5 year old son recently suffered a hypoxic brain injury resulting in motor and speech disabilities. There are several clinical trials underway for TBI in adults. My questions are:
Will the results be scalable to pediatric use and how long do you think it would take before it is available to children?
I’m wondering why the current trials have chosen to go the route of intracranial injections as opposed to something slightly less invasive like an intrathecal injection?
Is there a time window period in which stem cells should be administered by, after which the administration is deemed not effective?
Dr. Kelly Shepard: TBI and other injuries of the nervous system are characterized by a lot of inflammation at the time of injury, which is thought to interfere with the healing process- and thus some approaches are intended to be delivered after that inflammation subsides. However, we are aware of approaches that intend to deliver a therapy to a chronic injury, or one that has occurred previously. Thus, the answer to this question may depend on how the intended therapy is supposed to work. For example, is the idea to grow new neurons, or is it to promote the survival of neurons of other cells that were spared by the injury? Is the therapy intended to address a specific symptom, such as seizures? Is the therapy intended to “fill a gap” left behind after inflammation subsides, which might not restore all function but might ameliorate certain symptoms.? There is still a lot we don’t understand about the brain and the highly sophisticated network of connections that cannot be reversed by only replacing neurons, or only reducing inflammation, etc. However, if trials are well designed, they should yield useful information even if the therapy is not as effective as hoped, and this information will pave the way to newer approaches and our technology and understanding evolves.
We have had a doctor recommending administering just the growth factors derived from MSC stem cells. Does the science work that way? Is it possible to isolate the growth factors and boost the endogenous growth factors by injecting allogenic growth factors?
Dr. Stephen Lin: Several groups have published studies on the therapeutic effects in non-human animal models of using nutrient media from MSC cultures that contain secreted factors, or extracellular vesicles from cells called exosomes that carry protein or nucleic acid factors. Scientifically it is possible to isolate the factors that are responsible for the therapeutic effect, although to date no specific factor or combination of factors have been identified to mimic the effects of the undefined mixtures in the media and exosomes. At present no regulatory approved clinical therapy has been developed using this approach.
PREDATORY STEM CELL CLINICS
What practical measures are being taken to address unethical practitioners whose bad surgeries are giving stem cell advances a bad reputation and are making forward research difficult?Kathy Jean Schultz
Dr. Geoff Lomax: Terrific question! I have been doing quite a bit research into the history of this issue of unethical practitioners and I found an 1842 reference to “quack medicines.” Clearly this is nothing new. In that day, the author appealed to make society “acquainted with the facts.”
In California, we have taken steps to (1) acquaint patients with the facts about stem cell treatments and (2) advance FDA authorized treatments for unmet medical needs.
First, CIRM work with Senator Hernandez in 2017 to write a law the requires provides to disclose to patient that a stem cell therapy has not been approved by the Food and Drug administration.
We continue to work with the State Legislature and Medical Board of California to build on policies that require accurate disclosure of the facts to patients.
Second, our clinical trial network the — Alpha Stem Cell Clinics – have supported over 100 FDA-authorized clinical trials to advance responsible clinical research for unmet medical needs.
I’m curious if adipose stem cell being used at clinics at various places in the country is helpful or beneficial?Cheri Hicks
Adipose tissue has been widely used particularly in plastic and reconstructive surgery. Many practitioners suggest adipose cells are beneficial in this context. With regard to regenerative medicine and / or the ability to treat disease and injury, I am not aware of any large randomized clinical trials that demonstrate the safety and efficacy of adipose-derived stem cells used in accordance with FDA guidelines.
I went to a “Luncheon about Stem Cell Injections”. It sounded promising. I went thru with it and got the injections because I was desperate from my knee pain. The price of stem cell injections was $3500 per knee injection. All went well. I have had no complications, but haven’t noticed any real major improvement, and here I am a year later. My questions are:
1) I wonder on where the typical injection cells are coming from?
2) I wonder what is the actual cost of the cells?
3) What kind of results are people getting from all these “pop up” clinics or established clinics that are adding this to there list of offerings?
Dr. Geoff Lomax: You raise a number of questions and point here; they are all very good and it’s is hard to give a comprehensive response to each one, but here is my reaction:
There are many practitioners in the field of orthopedics who sincerely believe in the potential of cell-based treatments to treat injury / pain
Most of the evidence presented is case reports that individuals have benefited
The challenge we face is not know the exact type of injury and cell treatments used.
Well controlled clinical trials would really help us understand for what cells (or cell products) and for what injury would be helpful
Prices of $3000 to $5000 are not uncommon, and like other forms of private medicine there is often a considerable mark-up in relation to cost of goods.
You are correct that there have not been reports of serious injury for knee injections
However the effectiveness is not clear while simultaneously millions of people have been aided by knee replacements.
Do stem cells have benefits for patients going through chemotherapy and radiation therapy?Ruperto
Dr. Kelly Shepard: The idea that a stem cell therapy could help address effects of chemotherapy or radiation is being and has been pursued by several investigators over the years, including some with CIRM support. Towards the earlier stages, people are looking at the ability of different stem cell-derived neural cell preparations to replace or restore function of certain brain cells that are damaged by the effects of chemotherapy or radiation. In a completely different type of approach, a group at City of Hope is exploring whether a bone marrow transplant with specially modified stem cells can provide a protective effect against the chemotherapy that is used to treat a form of brain cancer, glioblastoma. This study is in the final stage of development that, if all goes well, culminates with application to the FDA to allow initiation of a clinical trial to test in people.
Dr. Ingrid Caras: That’s an interesting and valid question. There is a Phase 1 trial ongoing that is evaluating a novel type of stem/progenitor cell from the umbilical cord of healthy deliveries. In animal studies, these cells have been shown to reduce the toxic effects of chemotherapy and radiation and to speed up recovery. These cells are now being tested in a First-in-human clinical trial in patients who are undergoing high-dose chemotherapy to treat their disease.
There is a researcher at Stanford, Michelle Monje, who is investigating that the role of damage to stem cells in the cognitive problems that sometimes arise after chemo- and radiation therapy (“chemobrain”). It appears that damage to stem cells in the brain, especially those responsible for producing oligodendrocytes, contributes to chemobrain. In CIRM-funded work, Dr. Monje has identified small molecules that may help prevent or ameliorate the symptoms of chemobrain.
Is it possible to use a technique developed to fight one disease to also fight another? For instance, the bubble baby disease, which has cured (I think) more than 50 children, may also help fight sickle cell anemia? Don Reed.
Dr. Lisa Kadyk: Hi Don. Yes, the same general technique can often be applied to more than one disease, although it needs to be “customized” for each disease. In the example you cite, the technique is an “autologous gene-modified bone marrow transplant” – meaning the cells come from the patient themselves. This technique is relevant for single gene mutations that cause diseases of the blood (hematopoietic) system. For example, in the case of “bubble baby” diseases, a single mutation can cause failure of immune cell development, leaving the child unable to fight infections, hence the need to have them live in a sterile “bubble”. To cure that disease, blood stem cells, which normally reside in the bone marrow, are collected from the patient and then a normal version of the defective gene is introduced into the cells, where it is incorporated into the chromosomes. Then, the corrected stem cells are transplanted back into the patient’s body, where they can repopulate the blood system with cells expressing the normal copy of the gene, thus curing the disease.
A similar approach could be used to treat sickle cell disease, since it is also caused by a single gene mutation in a gene (beta hemoglobin) that is expressed in blood cells. The same technique would be used as I described for bubble baby disease but would differ in the gene that is introduced into the patient’s blood stem cells.
Is there any concern that CIRM’s lack of support in basic research will hamper the amount of new approaches that can reach clinical stages? Jason
Dr. Kelly Shepard: CIRM always has and continues to believe that basic research is vital to the field of regenerative medicine. Over the past 10 years CIRM has invested $904 million in “discovery stage/basic research”, and about $215 million in training grants that supported graduate students, post docs, clinical fellows, undergraduate, masters and high school students performing basic stem cell research. In the past couple of years, with only a limited amount of funds remaining, CIRM made a decision to invest most of the remaining funds into later stage projects, to support them through the difficult transition from bench to bedside. However, even now, CIRM continues to sponsor some basic research through its Bridges and SPARK Training Grant programs, where undergraduate, masters and even high school students are conducting stem cell research in world class stem cell laboratories, many of which are the same laboratories that were supported through CIRM basic research grants over the past 10 years. While basic stem cell research continues to receive a substantial level of support from the NIH ($1.8 billion in 2018, comprehensively on stem cell projects) and other funders, CIRM believes continued support for basic research, especially in key areas of stem cell research and vital opportunities, will always be important for discovering and developing new treatments.
What is the future of the use of crispr cas9 in clinical trials in california/globally. Art Venegas
Dr. Kelly Shepard: CRISPR/Cas9 is a powerful gene editing tool. In only a few years, CRISPR/Cas9 technology has taken the field by storm and there are already a few CRISPR/Cas9 based treatments being tested in clinical trials in the US. There are also several new treatments that are at the IND enabling stage of development, which is the final testing stage required by the FDA before a clinical trial can begin. Most of these clinical trials involving CRISPR go through an “ex vivo” approach, taking cells from the patient with a disease causing gene, correcting the gene in the laboratory using CRISPR, and reintroducing the cells carrying the corrected gene back into the patient for treatment. Sickle cell disease is a prime example of a therapy being developed using this strategy and CIRM funds two projects that are preparing for clinical trials with this approach. CRISPR is also being used to develop the next generation of cancer T-cell therapies (e.g. CAR-T), where T-cells – a vital part of our immune system – are modified to target and destroy cancer cell populations. Using CRISPR to edit cells directly in patients “in vivo” (inside the body) is far less common currently but is also being developed. It is important to note that any FDA sanctioned “in vivo” CRISPR clinical trial in people will only modify organ-specific cells where the benefits cannot be passed on to subsequent generations. There is a ban on funding for what are called germ line cells, where any changes could be passed down to future generations.
CIRM is currently supporting multiple CRISPR/Cas9 gene editing projects in California from the discovery or most basic stage of research, through the later stages before applying to test the technique in people in a clinical trial.
While the field is new – if early safety signals from the pioneering trials are good, we might expect a number of new CRISPR-based approaches to enter clinical testing over the next few years. The first of these will will likely be in the areas of bone marrow transplant to correct certain blood/immune or metabolic diseases, and cancer immunotherapies, as these types of approaches are the best studied and furthest along in the pipeline.
Explain the differences between gene therapy and stem cell therapy?Renee Konkol
Dr. Stephen Lin: Gene therapy is the direct modification of cells in a patient to treat a disease. Most gene therapies use modified, harmless viruses to deliver the gene into the patient. Gene therapy has recently seen many success in the clinic, with the first FDA approved therapy for a gene induced form of blindness in 2017 and other approvals for genetic forms of smooth muscle atrophy and amyloidosis.
Stem cell therapy is the introduction of stem cells into patients to treat a disease, usually with the purpose of replacing damaged or defective cells that contribute to the disease. Stem cell therapies can be derived from pluripotent cells that have the potential to turn into any cell in the body and are directed towards a specific organ lineage for the therapy. Stem cell therapies can also be derived from other cells, called progenitors, that have the ability to turn into a limited number of other cells in the body. for example hematopoietic or blood stem cells (HSCs), which are found in bone marrow, can turn into other cells of the blood system including B-cells and T-cells: while mesenchymal stem cells (MSCs), which are usually found in fat tissue, can turn into bone, cartilage, and fat cells. The source of these cells can be from the patient’s own body (autologous) or from another person (allogeneic).
Gene therapy is often used in combination with cell therapies when cells are taken from the patient and, in the lab, modified genetically to correct the mutation or to insert a correct form of the defective gene, before being returned to patients. Often referred to as “ex vivo gene therapy” – because the changes are made outside the patient’s body – these therapies include Chimeric Antigen Receptor T (CAR-T) cells for cancer therapy and gene modified HSCs to treat blood disorders such as severe combined immunodeficiency and sickle cell disease. This is an exciting area that has significantly improved and even cured many people already.
Currently, how can the outcome of CIRM stem cell medicine projects and clinical trials be soundly interpreted when their stem cell-specific doses are not known?James L. Sherley, M.D., Ph.D., Director. Asymmetrex, LLC
Dr. Stephen Lin: Stem cell therapies that receive approval to conduct clinical trials must submit a package of data to the FDA that includes studies that demonstrate their effectiveness, usually in animal models of the disease that the cell therapy is targeting. Those studies have data on the dose of the cell therapy that creates the therapeutic effect, which is used to estimate cell doses for the clinical trial. CIRM funds discovery and translational stage awards to conduct these types of studies to prepare cell therapies for clinical trials. The clinical trial is also often designed to test multiple doses of the cell therapy to determine the one that has the best therapeutic effect. Dosing can be very challenging with cell therapies because of issues including survival, engraftment, and immune rejection, but CIRM supports studies designed to provide data to give the best estimate possible.
Is there any research on using stem cells to increase the length of long bones in people?” For example, injecting stem cells into the growth plates to see if the cells can be used to lengthen limbs.Sajid
Dr. Kelly Shepard: There is quite a lot of ongoing research seeking ways to repair bones with stem cell based approaches, which is not the same but somewhat related. Much of this is geared towards repairing the types of bone injuries that do not heal well naturally on their own (large gaps, dead bone lesions, degenerative bone conditions). Also, a lot of this research involves engineering bone tissues in the lab and introducing the engineered tissue into a bone lesion that need be repaired. What occurs naturally at the growth plate is a complex interaction between many different cell types, much of which we do not fully understand. We do not fully understand how to use the cells that are used to engineer bone tissue in the lab. However, a group at Stanford, with some CIRM support, recently discovered a “skeletal stem cell” that exists naturally at the ends of human bones and at sites of fracture. These are quite different than MSCs and offer a new path to be explored for repairing and generating bone.
Health Citizenship panel discussion at Partnering for Cures: L to R: Lucia Savage, Roni Zeiger, Claudia Williams, Jennifer Mills, Kathy Hudson, Beth Meagher
One of the buzz phrases in healthcare today is “patient engagement”. It seems that you can’t go to a medical or scientific conference without coming across a panel discussion on the topic. A recent Partnering For Cures* event in San Francisco was no exception. But here the conversation took on a very different tone, one that challenged what the term meant and then said that if we are really serious about engaging patients, then doctors and drug companies need to change the way they think and operate.
That tone was set from the start of the discussion when moderator Claudia Williams said even the term “patient engagement” suggests that it is something “being imposed, or at least allowed, from the outside; by experts and doctors and those in charge.”
Williams quoted Erin Moore, the mother of a young boy with cystic fibrosis saying “No one is more engaged than the patient. I want the experts, the doctors, the pharmaceutical companies to be engaged.”
Need to train doctors
Dr. Roni Zeiger, the former Chief Health Strategist at Google, said doctors aren’t trained to truly listen to and engage with patients, and that has to change:
“I sometimes think of myself as a recovering paternal physician. When I listen to and learn from patients and families I am surprised, every time, at the breadth and depth of the conversations. All of the things that we, in the medical field, do from designing a waiting room to designing a clinical trial to deciding when and how to have a conversation, we bring a tremendous amount of assumptions to those. And those assumptions are often wrong. I think that on a daily basis we should be looking at the key work we do and ask are there assumptions here I should throw away and talk to those I serve and get their help in redesigning things in a way that makes more sense.”
Jennifer Mills, the Director of Patient Engagement (that phrase again) at biotech giant Genentech, said those mistakes are made by everyone in the field:
“The biggest assumption for me is thinking about patients with a capital P, as a homogeneous group, instead of realizing they are also individuals. We need to address them as a group and as individuals depending on the circumstances.”
Caregivers count too
For example as people get older and rely on a partner or spouse to take care of them it may be important to not just engage with the patient but also with the caregiver. And the needs for each of them may not be the same.
At that point the conversation turned to the use of data. Lucia Savage, the Chief Privacy and Regulatory Officer at Omada Health, said it is going to be increasingly important to give people control over their own medical data, and sometimes the medical data of others.
“Caregivers need access to healthcare records. For example, I can check my mom’s labs. If I message her doctors they can share that information with me. It’s great because it helps us help her lead an independent life as an 80 year old.”
Savage also pointed out that we need to be careful how we interpret data. She said she could go shopping and buy three extra-large bags of potato chips. On the face of it that doesn’t look good. But did she buy those chips for herself or her daughter’s soccer team. The data is the same. The implications are very different.
Partnership not patronizing
The discussion ended with an attempt to outline what being a good health citizen means. Just as citizenship involves both rights and responsibilities on the part of the individual and society, health citizenship too involves rights and responsibilities on the part of the individual and the biomedical research and health care world. Patients deserve to be treated as individuals who have a vested interest in their own health. They don’t need “experts” to talk down or patronize them or assume they know best.
Mills says she is seeing progress in this area:
“Companies are moving from assuming what patients need to asking what they need. We once assumed that if we were in the therapeutic area long enough we didn’t need to ask what patients need. I’m seeing that change.”
Deloitte Consulting’s Beth Meagher said we need to look beyond technology and focus on the people:
“Humility is going to be the killer app. The true innovators are really being humble and realizing that to have the kind of impact they are looking for, there is a need to work in a way they haven’t before. “
*Partnering for Cures is a project of Michael Milken’s FasterCures, whose goal is to save lives by speeding up and improving the medical research system.
Today, in a new video, I highlight a brave young patient, Ronnie, and his parents who decided to participate in a CIRM-funded clinical trial run by St. Jude Children’s Research Hospital and UC San Francisco in an attempt to save Ronnie’s life from an often-fatal disease called severe combined immunodeficiency (SCID). This disorder, also known as bubble baby disease, leaves newborns without a functioning immune system which can turn a simple cold into a potentially deadly infection.
Watch this story’s happy ending in the video above.
This week in Washington DC a delegation from the stem cell advocacy group Texans for Cures is meeting with members of Congress from both parties. The focus of the meetings are three bills promoting “Right to Try” legislation. Supporters of the bills say they will empower patients battling terminal illness. Texans for Cures say, quite the contrary, that these laws will endanger patients. In this guest blog, Texans for Cures explain why they feel these laws are bad.
In 2014, the Goldwater Institute published a policy report titled, “Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment.”[i] The report calls for states to pass “Right to Try” legislation as a means to reclaim patients’ medical autonomy and right to determine their own medical treatment.
This policy recommendation is built on the theory that the Food and Drug Administration (FDA) should not be able to restrict terminal patients’ access to potentially life-saving treatments so long as the treatment has been tested for basic safety. While this idea may seem immediately appealing, the policy undermines medical research in several ways that are harmful to the development of new treatments.
Texans for Cures opposes this legislation because it harms the sound development of treatments for future patients on the mere chance that it may provide relief to current patients that have received a terminal diagnosis. In short, Right to Try policies ignore the attendant risks and overemphasize the potential benefits.
“Right to Try” Model Legislation and State Enacted Variants
The Goldwater Institute’s policy report included model legislation for interested legislators, which it summed up as follows:
Simply stated, Right to Try allows a patient to access investigational medications that have passed basic safety tests without interference by the government when the following conditions are met:
The patient has been diagnosed with a terminal disease;
The patient has considered all available treatment options;
The patient’s doctor has recommended that the investigational drug, device, or biological product represents the patient’s best chance at survival;
The patient or the patient’s guardian has provided informed consent; and
The sponsoring company chooses to make the investigational drug available to patients outside the clinical trial.
Since the Goldwater Institute published this policy report in 2014, 33 states have enacted Right to Try laws.[ii] These laws contain minor variations from the model legislation, but each operates similarly to limit the FDA’s oversight roll.
Right to Try is Loosely Grounded in the Constitution and May Require Federal Action
Due to the fact that these laws may infringe on the FDA’s authority over drug development and distribution, the policy report attempts to ground Right to Try in one’s constitutional right to liberty. This constitutional underpinning is loose and is not firmly supported by Supreme Court precedent.[iii] With the constitutional basis of Right to Try resting on a weak foundation, it is important for Right to Try proponents to pass a complimentary Right to Try statute on the federal level in Congress.
There are three bills actively working through the Congressional process that would prohibit the FDA or any other federal agency from interfering with a patient’s Right to Try: H.R. 878 by Representative Biggs,[iv] H.R. 2368 by Representative Fitzpatrick,[v] and S. 204 by Senator Johnson.[vi] Each of these bills shares three common provisions, while H.R. 2368 has two additional provisions:
Prohibition on federal action
No use of outcomes
Provisions Unique to H.R. 2368:
Manufacturers are not required to make treatments available
Permits manufacturers to receive compensation or recover costs
All three of the federal bills would remove the FDA’s ability to intervene in state Right to Try programs. They also create a liability shield for any producer, manufacturer, distributor, prescriber, dispenser, possessor, or user participating in the program. And finally, each prohibits the use of outcomes from patients participating in Right to Try as a criteria for FDA review of the treatment. This means that harmed patients would have limited or no legal recourse, and the FDA may need another Act of Congress to grant them the authority to intervene in any programs that prove to be dangerous. However, it may be difficult to know if these programs are harming patients or not, because the bills do not provide any mechanism for tracking outcomes and using that information for oversight.
Each bill is drafted in a way that would remove FDA oversight authority and would allow states to proceed with Right to Try policies and grants states broad discretion to tailor these programs without federal oversight. However, H.R. 2368 contains two additional provisions that would compliment and potentially override state statute. First, the bill gives manufacturers the authority to deny patients access to investigational treatments, which is consistent with the Goldwater Institute’s model legislation. Second, the bill allows manufacturers to receive compensation or recover costs involved in making the drug available to patients. This second provision is particularly problematic in that it would allow manufacturers to charge patients for unproven treatments unless they were explicitly prohibited from doing so by state law.
How Right to Try Laws Structurally Harm the Research Process
Right to Try laws create a number of problematic incentives and penalties that would likely harm the long term development of new therapies. First and foremost, under Right to Try, patients will be able to bypass the clinical trial process, request investigational treatments, and pay the cost of the drug, rather than enter into a clinical trial. Given that clinical trials may involve the use of placebos, Texans for Cures is concerned that patients may choose to exercise Right to Try rather than participate in a clinical trial, because under Right to Try the patient avoids the possibility of receiving a placebo.
Additionally, there is no mechanism in the proposed bills for tracking outcomes of patients participating in Right to Try, and there is no mechanism for government intervention if Right to Try proves to be unreasonably risky.
Right to Try seeks to shield all participants from liability, meaning that patients who are harmed will have limited or no legal recourse, even if manufacturers or physicians are negligent. Furthermore, Right to Try laws typically allow manufacturers to recover the cost of manufacturing the treatment for participating patients, but cost is not defined. Does cost include the cost of research and development or is it exclusively the cost of creating that specific treatment? The ambiguity surrounding this term is a cause for concern, because companies may be tempted to use this ambiguity to cover a broader sets of costs than the authors intended.
Texans for Cures opposes this legislative effort because the program could potentially harm patients and, if it does, the law does not provide adequate safeguards or remedies. Additionally, the law does not require any monitoring of outcomes and is therefore unscientific in its approach to treatments that are currently undergoing clinical research.
The FDA is already working to ease the burdens associated with Expanded Access programs, which achieve the end that Right to Try desires: providing access to research drugs for terminal patients. The difference is that Expanded Access has additional safeguards and a mechanism for FDA intervention if treatment is found to be dangerous or harmful to the clinical trial process.
Finding scientifically sound treatments for patients in need is the primary concern of Texans for Cures. Texans for Cures sympathizes with, and its members have similarly experienced, the pain of losing loved ones. The hope and emotion involved in Right to Try laws is not to be taken lightly, but it is precisely because strong emotions can cloud our judgment that we, as a society, must approach the clinical trial process with a clear mental state. Texans for Cures believes that Right to Try will harm the long term development of new treatments and therefore asks for your help in fighting this legislative effort.
3 The Goldwater Institute’s sole source for constitutional grounding for this law comes from a concurrence by Justice Douglas in Doe v. Bolton, 410 U.S. 179, 218 (1973), where he noted that individuals have a “right to care for one’s health and person.” The Goldwater Institute appears to recognize the precarious footing of their model legislation, stating in their policy report, “Although the right of terminal patients to access investigational medications has not yet been recognized by the Supreme Court, it is consistent with and can be supported by existing precedent.”
Every day, we receive phone calls and emails from people who are desperately seeking our help. Sometimes they reach out on their own behalf, though often it’s for a family member or close friend. In every case, someone is suffering or dying from a disorder that has no available cure or effective treatment and they look to stem cell treatments as their only hope.
It’s heartbreaking to hear these personal stories that are unfolding in real time. Though they contact us from a wide range of places about a wide range of disorders, their initial set of questions are often similar and go something like this:
“Where can I find stem cell clinical trial for my condition?”
“What are my chances of being cured?”
“How much does it cost to be in a clinical trial?”
“How can I be sure it’s safe?”
We think anyone thinking about taking part in a clinical trial should consider these important questions. So, in addition to providing answers as we receive them through phone calls and emails, we wanted to find a way to reach out to as many people as possible. The result? The four-minute animation video you can watch below:
As mentioned in the video, the answers to these questions are only the tip of the iceberg for finding out if a particular clinical trial is right for you. The website, A Closer Look at Stem Cells, produced by the International Society for Stem Cell Research (ISSCR), is an excellent source for more advice on what things you should know before participating in a stem cell clinical trial or any experimental stem cell treatment.
To get anywhere you need a good map, and you need to check it constantly to make sure you are still on the right path and haven’t strayed off course. A year ago the CIRM Board gave us a map, a Strategic Plan, that laid out our course for the next five years. Our Annual Report for 2016, now online, is our way of checking that we are still on the right path.
I think, without wishing to boast, that it’s safe to say not only are we on target, but we might even be a little bit ahead of schedule.
The Annual Report is chock full of facts and figures but at the heart of it are the stories of the people who are the focus of all that we do, the patients. We profile six patients and one patient advocate, each of whom has an extraordinary story to tell, and each of whom exemplifies the importance of the work we support.
Brenden Whittaker: Cured
Two stand out for one simple reason, they were both cured of life-threatening conditions. Now, cured is not a word we use lightly. The stem cell field has been rife with hyperbole over the years so we are always very cautious in the way we talk about the impact of treatments. But in these two cases there is no need to hold back: Evangelina Padilla Vaccaro and Brenden Whittaker have been cured.
In the coming weeks we’ll feature our conversations with all those profiled in the Annual Report, giving you a better idea of the impact the stem cell treatments have had on their lives and the lives of their family. But today we just wanted to give a broad overview of the Annual Report.
The Strategic Plan was very specific in the goals it laid out for us. As an agency we had six big goals, but each Team within the agency, and each individual within those teams had their own goals. They were our own mini-maps if you like, to help us keep track of where we were individually, knowing that every time an individual met a goal they helped the Team get closer to meeting its goals.
As you read through the report you’ll see we did a pretty good job of meeting our targets. In fact, we missed only one and we’re hoping to make up for that early in 2017.
But good as 2016 was, we know that to truly fulfill our mission of accelerating treatments to patients with unmet medical needs we are going to have do equally well, if not even better, in 2017.
Part of The Stem Cellar blog series on 10 years of iPSCs.
This year, scientists are celebrating the 10-year anniversary of Shinya Yamanaka’s Nobel Prize winning discovery of induced pluripotent stem cells (iPSCs). These are cells that are very similar biologically to embryonic stem cells and can develop into any cell in the body. iPSCs are very useful in scientific research for disease modeling, drug screening, and for potential cell therapy applications.
However, with any therapy that involves testing in human patients, there are ethical questions that scientists, companies, and policy makers must consider. Yesterday, a panel of stem cell and bioethics experts at the Cell Symposium 10 Years of iPSCs conference in Berkeley discussed the ethical issues surrounding the translation of iPSC research from the lab bench to clinical trials in patients.
The panel included Shinya Yamanaka (Gladstone Institutes), George Daley (Harvard University), Christine Mummery (Leiden University Medical Centre), Lorenz Studer (Memorial Sloan Kettering Cancer Center), Deepak Srivastava (Gladstone Institutes), and Bioethicist Hank Greely (Stanford University).
iPSC Ethics Panel at the 10 Years of iPSCs Conference
Below is a summary of what these experts had to say about questions ranging from the ethics of patient and donor consent, genetic modification of iPSCs, designer organs, and whether patients should pay to participate in clinical trials.
How should we address patient or donor consent regarding iPSC banking?
Multiple institutes including CIRM are developing iPSC banks that store thousands of patient-derived iPSC lines, which scientists can use to study disease and develop new therapies. These important cell lines wouldn’t exist without patients who consent to donate their cells or tissue. The first question posed to the panel was how to regulate the consent process.
Christine Mummery began by emphasizing that it’s essential that companies are able to license patient-derived iPSC lines so they don’t have to go back to the patient and inconvenience them by asking for additional samples to make new cell lines.
George Daley and Hank Greely discussed different options for improving the informed consent process. Daley mentioned that the International Society for Stem Cell Research (ISSCR) recently updated their informed consent guidelines and now provide adaptable informed consent templates that can be used for obtaining many type of materials for human stem cell research. Daley also mentioned the move towards standardizing the informed consent process through a single video shared by multiple institutions.
Greely agreed that video could be a powerful way to connect with patients by using talented “explainers” to educate patients. But both Daley and Greely cautioned that it’s essential to make sure that patients understand what they are getting involved in when they donate their tissue.
Greely rounded up the conversation by reminding the audience that patients are giving the research field invaluable information so we should consider giving back in return. While we can’t and shouldn’t promise a cure, we can give back in other ways like recognizing the contributions of specific patients or disease communities.
Greely mentioned the resolution with Henrietta Lack’s family as a good example. For more than 60 years, scientists have used a cancer cell line called HeLa cells that were derived from the cervical cancer cells of a woman named Henrietta Lacks. Henrietta never gave consent for her cells to be used and her family had no clue that pieces of Henrietta were being studied around the world until years later.
“The Lacks family are quite proud and pleased that their mother, grandmother and great grandmother is being remembered, that they are consulted on various things,” said Hank Greely. “They aren’t making any direct money out of it but they are taking a great deal of pride in the recognition that their family is getting. I think that returning something to patients is a nice thing, and a human thing.”
What are the ethical issues surrounding genome editing of iPSCs?
The conversation quickly focused on the ongoing CRISPR patent battle between the Broad Institute, MIT and UC Berkeley. For those unfamiliar with the technique, CRISPR is a gene editing technology that allows you to cut and paste DNA at precise locations in the genome. CRISPR has many uses in research, but in the context of iPSCs, scientists are using CRISPR to remove disease-causing mutations in patient iPSCs.
George Daley expressed his worry about a potential fallout if the CRISPR battle goes a certain way. He commented, “It’s deeply concerning when such a fundamentally enabling platform technology could be restricted for future gene editing applications.”
The CRISPR patent battle began in 2012 and millions of dollars in legal fees have been spent since then. Hank Greely said that he can’t understand why the Institutes haven’t settled this case already as the costs will only continue to rise, but that it might not matter how the case turns out in the end:
“My guess is that this isn’t ultimately going to be important because people will quickly figure out ways to invent around the CRISPR/Cas9 technology. People have already done it around the Cas9 part and there will probably be ways to do the same thing for the CRISPR part.”
Christine Mummery finished off with a final point about the potential risk of trying to correct disease causing mutations in patient iPSCs using CRISPR technology. She noted that it’s possible the correction may not lead to an improvement because of other disease-causing genetic mutations in the cells that the patient and their family are unaware of.
Should patients or donors be paid for their cells and tissue?
Lorenz Studer said he would support patients being paid for donating samples as long as the payment is reasonable, the consent form is clear, and patients aren’t trying to make money off of the process.
Hank Greely said the big issue is with inducement and whether you are paying enough money to convince people to do something they shouldn’t or wouldn’t want to do. He said this issue comes up mainly around reproductive egg donation but not with obtaining simpler tissue samples like skin biopsies. Egg donors are given money because it’s an invasive procedure, but also because a political decision was made to compensate egg donors. Greely predicts the same thing is unlikely to happen with other cell and tissue types.
Christine Mummery’s opinion was that if a patient’s iPSCs are used by a drug company to produce new successful drugs, the patient should receive some form of compensation. But she said it’s hard to know how much to pay patients, and this question was left unanswered by the panel.
Should patients pay to participate in clinical trials?
George Daley said it’s hard to justify charging patients to participate in a Phase 1 clinical trial where the focus is on testing the safety of a therapy without any guarantee that there will be beneficial outcome to the patient. In this case, charging a patient money could raise their expectations and mislead them into thinking they will benefit from the treatment. It would also be unfair because only patients who can afford to pay would have access to trials. Ultimately, he concluded that making patients pay for an early stage trial would corrupt the informed consent process. However, he did say that there are certain, rare contexts that would be highly regulated where patients could pay to participate in trials in an ethical way.
Lorenz Studer said the issue is very challenging. He knows of patients who want to pay to be in trials for treatments they hope will work, but he also doesn’t think that patients should have to pay to be in early stage trials where their participation helps the progress of the therapy. He said the focus should be on enrolling the right patient groups in clinical trials and making sure patients are properly educated about the trial they are participating.
Thoughts on the ethics behind making designer organs from iPSCs?
Deepak Srivastava said that he thinks about this question all the time in reference to the heart:
Deepak Srivastava, Gladstone Institutes
“The heart is basically a pump. When we traditionally thought about whether we could make a human heart, we asked if we could make the same thing with the same shape and design. But in fact, that’s not necessarily the best design – it’s what evolution gave us. What we really need is a pump that’s electrically active. I think going forward, we should remove the constraint of the current design and just think about what would be the best functional structure to do it. But it is definitely messing with nature and what evolution has given us.”
Deepak also said that because every organ is different, different strategies should be used. In the case of the heart, it might be beneficial to convert existing heart tissue into beating heart cells using drugs rather than transplant iPSC-derived heart cells or tissue. For other organs like the pancreas, it is beneficial to transplant stem cell-derived cells. For diabetes, scientists have shown that injecting insulin secreting cells in multiple areas of the body is beneficial to Diabetes patients.
Hank Greely concluded that the big ethical issue of creating stem cell-derived organs is safety. “Biology isn’t the same as design,” Greely said. “It’s really, really complicated. When you put something into a biological organism, the chances that something odd will happen are extremely high. We have to be very careful to avoid making matters worse.”
For more on the 10 years of iPSCs conference, check out the #CSStemCell16 hashtag on twitter.
Part of The Stem Cellar series on ten years of iPS cells
For Chris Waters, the motivation behind her move from big pharmaceutical companies and biotech to starting a non-profit organization focused on rare diseases in children is simple: “What’s most important is empowering patient families and helping them accelerate research to the clinical solutions they so urgently need for their child ,” she says.
Chris is the founder of Rare Science. Their mission statement – Accelerating Cures for RARE Kids – bears a striking resemblance to ours here at CIRM, so creating a partnership between us just seemed to make sense. At least it did to Chris. And one thing you need to know about Chris, is that when she has an idea you should just get out of the way, because she is going to make it happen.
“The biggest gap in drug development is that we are not addressing the specific needs of children, especially those with rare diseases. We need to focus on kids. They are our future. If it takes 14 years and $2 billion to get FDA approval for a new drug, how is that going to help the 35% of the 200 million children across the world that are dying before 5 years of age because they have a rare disease? That’s why we created Rare Science. How do we help kids right now, how do we help the families? How do we make change?”
Banking on CIRM for help
One of the changes she wanted to make was to add the blood and tissue samples from one of the rare disease patient communities she works with to the CIRM Induced Pluripotent Stem Cell Bank. This program is collecting samples from up to 3,000 Californians – some of them healthy, some suffering from diseases such as autism, Alzheimer’s, heart, lung and liver disease and blindness. The samples will be turned into iPS cells – pluripotent stem cells that have the ability to be turned into any other type of cell in the body – enabling researchers to study how the diseases progress, and hopefully leading to the development of new therapies.
Lilly Grossman: photo courtesy LA Times
Chris says many kids with rare diseases can struggle for years to get an accurate diagnosis and even when they do get one there is often nothing available to help them. She says one San Diego teenager, Lilly Grossman, was originally diagnosed with Cerebral Palsy and it took years to identify that the real cause of her problems was a mutation in a gene called ADCY5, leading to abnormal involuntary movement. At first Lily’s family felt they were the only ones facing this problem. They have since started a patient family organization (ADCY5.org) that supports others with this condition.
“Even though we know that the affected individuals have the gene mutation, we have no idea how the gene causes the observable traits that are widely variable across the individuals we know. We need research tools to help us understand the biology of ADCY5 and other rare disease – it is not enough to just know the gene mutation. We always wanted to do a stem cell line that would help us get at these biological questions.”
But with little money to spend Chris faced what, for an ordinary person, might have been a series of daunting obstacles. She needed consent forms so that everyone donating tissue, particularly the children, knew exactly what was involved in giving samples and how those samples would be used in research. She also needed materials to collect the samples. In addition she needed to find doctors and sites around the world where the families were located to help with the sample collection. All of this was going to cost money, which for any non-profit is always in short supply.
So she went to work herself, creating a Research Participant’s Bill of Rights – a list of the rights that anyone taking part in medical research has. She developed forms explaining to children, teenagers and parents what happens if they give skin or blood samples as part of medical research, telling them how an individual’s personal medical health history may be used in research studies. And then she turned to medical supply companies and got them to donate the tubes and other materials that would be needed to collect and preserve the tissue and blood samples.
Even though ADCY5 is a very rare condition, Chris has collected samples from 42 individuals representing 13 different families, some affected with the condition as well as their unaffected siblings and parents. These samples come from families all around the world, from the US and Europe, to Canada and Australia.
“With CIRM we can build stem cell lines. We can lower the barrier of access for researchers who want to utilize these valuable stem cell lines that they may not have the resources to generate themselves. The cell lines, in the hands of researchers, can potentially accelerate understanding of the biology. They can help us identify targets to focus on for therapies. They can help us screen currently approved medications or drugs, so we have something now that could help these kids now, not 14 years from now.”
The samples Chris collects will be made available to researchers not just here in the US, but around the world. Chris hopes this program will serve as a model for other rare diseases, creating stem cell lines from them to help close the gap between discovery research and clinical impact.
Rare bears for rare disease
But in everything she does, in the end it always comes down to the patient families. Chris says so many children and families battling a rare disease feel they are alone. So she created with her team, the RARE Bear program to let them know they aren’t alone, that they are part of a worldwide community of support. She says each bear is handmade by the RARE Bear Army which spans 9 countries including 45 states in the US. Each RARE Bear is different, because “they are all one of a kind bears for one of a kind kids. And that’s why we are here, to help rare kids one bear at a time.” The RARE Bear program, also helps with rare disease awareness, patient outreach and rare disease community building which is key for RARE Science Research Programs.
It’s working. Chris recently got this series of photos and notes from the parents of a young girl in England, after they got their bear.
“I wanted to say a huge heartfelt thank you for my daughters Rare bear. It arrived today to Essex, England & as you can see from my pictures Isabella loves her already! We have named her Faith as a reminder to never give up!”