Cell therapy for Huntington’s Disease: learning from failure

Dear Professor Stoessl,

We write in response to the editorial by Albin and Kordower¹, “A failed future”, which offers a perspective on the MIG-HD foetal cell transplantation study in Huntington’s disease (HD) ². Whilst MIG-HD did not achieve a positive clinical outcome, Albin and Kordower’s critique of that study provides critical points of interpretation that we believe incorrect. In particular, we reject their categorical rejection of cell therapy as a regenerative treatment option for HD on the basis of a single phase II study of foetal cell transplantation. Indeed, Albin and Kordower highlight the confounds potentially caused by protocol changes during MIG-HD that emphasise the exploratory nature of this trial. Cell therapy has advanced substantially since MIG-HD was initiated; we now have fuller understanding of the cellular phenotypes and interactions that go awry in HD, and thus a clearer understanding of cell-based strategies that might be used in its treatment. We suggest that Albin and Kordower make unwarranted predictions of future failure – effectively “throwing out the baby with bath water” - based upon an overly broad interpretation of MIG-HD, leading them to a conclusion that is neither justified nor cognizant of the current science, and does a disservice to current work in the field.

MIG-HD focussed on achieving neural circuit reconstruction through transplanting striatal precursors isolated from foetal ganglionic eminence. It built on preclinical data and previous pilot human studies³ which constituted proof-of-concept that transplants can improve function, and that this may not require every element of pathology to be addressed; something borne out in Parkinson’s disease transplant studies where pathology also exists outside the key CNS target of cell therapy⁴. The limitations of foetal-derived donor cells stimulated research to derive candidate therapeutic progenitors (glial as well as neuronal⁵) from human pluripotent stem cells. Such cell products vary in their intended functions and therapeutic goals (e.g. cell replacement, neuroprotection) with numerous reports of significant functional benefits (e.g.⁶). It is uninformative to lump these different products, targets and therapeutic aims together, and misleading to dismiss them all on the basis of a single phase II study initiated two decades ago.

We believe a more productive approach is to formulate an honest, comprehensive appraisal of foreseeable challenges, in order to develop a rational road map for moving forward. There should be due consideration of the limitations of MIG-HD and previous studies, leading to new perspectives on the design and implementation of clinical trials of cell therapies in HD (as reviewed in⁷). Indeed, publication and informed analysis of such negative data is precisely how we may best ensure future success. To facilitate this we established Stem Cells for HD (SC4HD: https://www.sc4hd.org/), a global consortium of experts working in various areas of cell therapy. The group invites external peer review and is developing evidence-based guidance documents for the establishment of best practices in the field. We believe that this is the right process by which to assess whether the complex, but potentially powerful, strategy of cell-based therapies can have a place in the treatment of HD.