The future of brain repair: an interview with Jack Price

Written by Jack Price (King’s College London, UK)

Jack Price is a Professor of Developmental Neurobiology at King’s College London (UK), where he is part of the Institute of Psychiatry, Psychology & Neuroscience. He helped develop the first ever cell therapy to enter a clinical trial in Europe for a neurodegenerative disorder, known as the PISCES trial for ischemic stroke. From 2016 until last year, he was the Head of the Division of Advanced Therapies at the Medicines and Healthcare products Regulatory Agency (MHRA; London, UK). As part of his role at the MHRA, he was also the Director of the UK Stem Cell Bank.

In this interview, Jack speaks to us about his recently published book entitled, ‘The Future of Brain Repair: A Realist’s Guide to Stem Cell Therapy’, where he assesses the potential of stem cell therapies for treating brain disorders and why repairing the damaged nervous system is a challenge. Jack also discusses what significant breakthroughs have been made in stem cell therapies for neurological disorders, including what technological improvements are required to maximize their therapeutic effects as well as minimize their financial cost.


Could you provide us with an overview of what is discussed in your book?

In the book, I try to explain why repairing the damaged nervous system is such a challenge. Why can other tissues repair themselves so competently, yet the brain does such an inadequate job? I argue that stem cells could provide a way out of this conundrum and describe how efforts to pursue this have progressed for various disorders – for example, stroke, retinopathies, Parkinson’s disease and others. I describe the successes and failures, and how new technical developments have opened new opportunities. In addition to the technical challenges, I highlight the regulatory hurdles, the threats posed by ‘stem cell tourism’ and the ethical dilemmas surrounding clinical trials. Finally, I try to anticipate where the next breakthroughs will emerge and how the field might flourish in the future.

What have been the most significant breakthroughs in stem cell therapies for neurological disorders over the last few years?

All of us associated with regenerative medicine probably see induced pluripotent stem cell reprogramming as a breakthrough technology in our field, both as a source of new starting material for cell therapies and as a tool for disease modeling, but also as a conceptual step that opens many novel possibilities. Direct in situ reprogramming is among the most exciting of these new opportunities and is surely going to be implemented in clinical programs of the future.

Two further developments that excite me are the improvements in gene-editing technologies and in optogenetics. Both are challenging in ethical and regulatory terms but are sure to bring real advances.

Probably, if I had to pick a single advance that will make the biggest impact in the future, I would choose the combination of cell therapies with Class III medical devices – specifically substrates and supports for implanted cells and tissues. It has always struck me that our delivery of cell therapies to the brain at present is unbelievably primitive. Here we have the most complex structure imaginable – the human brain ­– packed with delicate cells and fibers, and how do we deliver therapy? Simply squirt in an aqueous slurry of cells. Surely we can do better, and indeed many researchers are now developing ‘patches’ where tissue, rather than individual cells, have been prepared supported by a matrix. This technology combined with another advance – organoids – looks very promising for the future.

In your opinion, are stem cell therapies a viable treatment option for brain disorders or will a combinatorial approach involving disease-modifying treatments be most beneficial?

This is a very good question and very difficult to answer at present. There are currently no licensed cell therapies for brain disorders. Until there are, the work of optimizing their use in relation to patient selection, dosing regimens and combination with existing therapies cannot really get underway. My prejudice, for what it’s worth, is a combination with other therapies will probably be beneficial. Progress in medicine is as much about optimizing the use of existing treatments, as it is in the derivation of new therapies. In the stroke field, for example, the preliminary data suggest that cell therapy may well alleviate chronic disability following a stroke. But we know that rehabilitation strategies also help. It seems to me that combining the two is likely to have a synergistic effect but whether that is true for all patients, or just some particular age cohort, or only for a specific period following cell therapy: this all has to be worked out.

How far are we from seeing stem cell therapies being licensed for neurological disorders? What clinical trials look the most promising?

I think licensed therapies are still a little way off. There are a number of promising avenues currently. I’m particularly impressed by the studies in the UK, USA and Japan in relation to age-related macular degeneration and Parkinson’s disease. These show the virtue in developing a thorough understanding of the disease pathology, the mode of action of the potential therapy, the critical quality attributes of the therapeutic product and the challenges around delivery. It is notable that cell therapies for Parkinson’s disease have been on the verge of succeeding now for at least three decades but still are not quite ready. Nonetheless, our understanding of what is required of a cell therapy in both of these arenas has improved enormously, demonstrating the virtue of building solid foundations. This is a lesson some have yet to learn, as demonstrated by some of the clinical failures over the last few years. For instance, I recently reviewed cell therapy trials in autism. This is a clear example, in my opinion, where clinical trials have come way too soon, long before a sufficiently strong scientific basis for the therapy had been established.

What technological/protocol improvements are required to maximize the therapeutic effects and minimize the financial cost of stem cell therapies for neurological disorders?

There are so many. I firmly believe that the future for cell therapies has to be allogeneic. If we are to produce medicines that are to meet true unmet medical need, then we have to steer around the niche medicines, only affordable by a few. Allogeneic cells have to be protected against immune rejection, so for me, the technologies aimed at generating universal donor cells are pivotal. I am impressed by the efforts to engineer HLA expression (though some of my immunology colleagues are still somewhat skeptical). I really wish those researchers well.

In the manufacturing space, there is a series of linked issues that need serious work. I call it the ‘what’s in the tube’ problem. As we don’t understand the mode of action of many cell therapy products, particularly those for CNS disorders, we cannot devise appropriate potency assays. As we cannot measure potency with any veracity, we cannot ascertain with certainty which cells in a culture are therapeutically active and which are not. We end up with mixed populations of cells, with only a guess at which work, which do nothing and which might be toxic. This train of uncertainty has to be broken if we are to produce consistent, effective medicines.


An extended version of this interview can be found on our sister site, RegMedNet, where Jack highlights the dangers that stem cell therapies pose to patients when presented as ‘miracle cures’. Click here to read the extended interview >>>

Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.

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