Neurology Central

Neuroregeneration: pipelines, trials and challenges – an interview with the California Institute for Regenerative Medicine

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As part of our Spotlight on neuroregeneration, we spoke to Helen Budworth, Kent Fitzgerald (both Science Officers) and Kevin McCormack (Senior Director Public Communications & Patient Advocate Outreach) from the California Institute for Regenerative Medicine (CIRM; CA, USA). They tell us more about CIRM’s current clinical portfolio and discovery pipeline, as well as the challenges involved in bringing neuroregenerative therapies to the clinic, and where we could be 10 years from now.

First, please could you tell us about your backgrounds? How did you both become interested in regenerative medicine?

HB: I completed my studies in the UK with a BSc in Genetics and Microbiology from the University of Liverpool and a DPhil in Biochemistry from the University of Oxford (both UK). My academic background is in the genetics of rare diseases and I studied these using a variety of model organisms including those with remarkable regenerative capabilities such as Planaria. I spent a number of years at Lawrence Berkeley National Laboratory (CA, USA) conducting cellular studies of diseases including Huntington’s disease, various ataxias, DNA repair deficiencies and cancers.

KF: Much of my academic and professional career has centered around neurodegenerative diseases. Working in this space in the context of drug discovery and development one becomes painfully aware of the limited therapeutic interventions currently available to those suffering from degenerative diseases. Regenerative medicine is at a critical inflection point where knowledge generated over the past decade-plus is at a point where it can be applied to clinical evaluation. CIRM has been at the forefront of these developments and my previous experience in translational science gives me a chance to help push our funded projects toward clinical application.

Can you tell us a little about CIRM? What do your roles there entail?

HB: At CIRM our mission is to accelerate stem cell treatments to patients with unmet medical needs and this mission guides all our activities. I am a Senior Science Officer in the Therapeutics Group at CIRM. My role includes recruiting high quality regenerative medicine programs at the clinical and late-stage preclinical stages to apply to CIRM for funding, and enabling CIRM-funded investigators to drive successful programs to next stages of development.

KF: As Helen mentioned, all of our job roles point to enabling the CIRM mission of accelerating therapies to patients. In my role as a Senior Science Officer / Program Officer in the Discovery and Translation group, I manage a diverse portfolio of CIRM-funded projects at this stage of development. Management from the Science Officer end involves acting as an external resource for project PIs where I can use my own expertise as well as other CIRM resources to increase the likelihood scientific success and advancement to the next stage of development. I also work with prospective applicants (for funding) to align their projects with the appropriate CIRM program.

What are CIRM’s focuses at the Discovery/Translational stage of neuroregeneration research? [userpro

KF: The goals of the Discovery/Translational programs are to identify candidates that are ready for translational stage activities leading to a Pre-IND filing with the FDA. These candidates can be therapeutics like cell therapies or other agents acting directly on stem/progenitor cells, or technologies enabling the use of stem cell / regenerative medicine like diagnostic tests, medical devices, or tools. We see a lot of applications in the Alzheimer’s, Parkinson’s, Huntington’s, ALS, multiple cclerosis, spinal cord injury and stroke therapeutic areas, but also smaller indications like Rett syndrome, spinal muscular atrophy and  Canavan disease.

Can you tell us about CIRM’s clinical portfolio?

HB: To date CIRM has funded 33 clinical trials, and currently has more than 10 programs preparing an IND to allow initiation of clinical trials within the next year. The CIRM clinical portfolio includes programs in neurologic disorders, ophthalmology, hematology, infectious disease, oncology, musculoskeletal, cardiovascular, metabolic and other indications. Clinical programs in neuroregeneration include spinal cord injury, ALS, stroke, and Huntington’s disease.

Want to read more on neuroregeneration? Check out our Spotlight here

What would you say are the core challenges in bringing regenerative therapies to the clinic, particularly in the treatment of neurological disease? How can these challenges be addressed?

HB: Some of the key challenges in regenerative medicine, and this is true for neurological disease, include selecting the optimal cell source, stage of differentiation and characterization of the cells. With neurological disease in particular; the timing of the therapy during the course of the disease or injury, dosing, and localization of the cell delivery are all critical variables that have to be fully determined to enable successful treatment. CIRM programs are dedicated to addressing these challenges and CIRM believes in funding multiple approaches to enable us to uncover the best solutions, and to allow us to deliver on our mission to accelerate the therapies to patients.

KF: In addition to Helen’s comments I would add that clinical application of regenerative medicine strategies is still young as a field. We’ve seen so many historical failures in the neurodegenerative space using traditional therapeutic strategies, and regenerative medicine by its very nature approaches these problems from a different angle. Taking these highly innovative approaches and getting them into the more traditional rigorous regulatory environment is vital to proper clinical evaluation and ultimate success or failure.

Additionally, in the neurology space we often deal with issues around long-term cell engraftment, immune rejection, target innervation and cell phenotype, just to name a few.  While the field has a sense for the requirements in these areas, it will ultimately be clinical evaluation that helps to define critical aspects around a given approach. As we know from traditional drug strategies in neurodegenerative disease, a hypothesis doesn’t always lead to success.

In your opinion, what has been the most significant advancement in regenerative medicine in the past decade or so?

KM: The past decade has seen so much progress on so many fronts that it’s hard to pinpoint one thing, but there are a few that certainly stand out.

1) Shinya Yamanaka and induced pluripotent stem (iPS) cells. This was certainly a game changer in a big way, creating a whole new kind of pluripotent cell and one that gave us an array of new tools to better understand what’s happening in particular cells affected by disease, and to create new models for testing potential therapies against those diseases. This has led to the possibility of an individual’s own cells being used to treat their disease, avoiding the fear of rejection that comes with using cells from a donor. The fact that iPS cells are already being used in clinical trials shows how fast the research using them is moving along.

2) CRISPR–Cas9. This is so new that we are still just beginning to explore how important it could be. It gives us a whole new way of editing genes, one that theoretically could enable us to correct problems in an embryo before it is even implanted in the womb, and allow us to eliminate deadly inherited conditions such as Huntington’s. But along with that promise comes some serious concerns about our ability to use it safely and not cause off-target mistakes that could have profound consequences for the child. It also is generating enormous ethical concerns about the ways it could be misused to create so-called “designer babies”, ones that have artificially increased intelligence or very specific physical characteristics such as increased height, blue eyes, etc.

What developments are you most excited to see in the future and where do you think we could be in 10 years’ time?

KM: Predicting the future is never easy and in science it is never wise; too often it leads to unrealistic expectations in the public, and frustration when hoped-for treatments and cures don’t materialize quickly. However, there are some indications of where we could be in 10 years.

With more and more programs reaching the clinical trial stage, we are finally getting a chance to see if these therapies work in people. The lessons we learn from this clinical research, even when those therapies don’t work as hoped, will be invaluable in guiding future research.

Less than 10 years after Yamanaka discovered iPS cells, we are already seeing them being tested in people in clinical trials. In the years to come we may see more and more therapies based on iPS technology in the clinic, opening up the possibility of more personalized therapies, using a patient’s own cells to treat their disease or disorder.

Combination therapies are already showing great promise in not just treating, but curing some immune disorders such as Severe Combined Immunodeficiency (SCID or “bubble baby disease”). It’s hoped we will be able to extend those techniques to treating and even curing other conditions such as Sickle Cell Anemia and possibly even HIV/AIDS. We are also seeing a growing number of researchers combining stem cells and immune boosting approaches to fighting cancer, the so-called CAR T cellular therapies. These are showing great promise and it’s hoped they will offer options to treating blood cancers and allow us to move away from the traditional toxic chemotherapy-based treatments.

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