An overview of the iterative process needed to address current biological and clinical challenges in order to improve reliability of future cell therapy trials in Huntington's disease.
Abstract
Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around twenty years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin‐lowering strategies, some of which are in Stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvem ents yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (non‐fetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multi‐site MIG‐HD study, and consider how this data may be used to inform future cell therapy trials.
© AlphaMed Press 2020
Significance Statement
Cell therapy is the only approach currently focused on structural and functional restoration in Huntington's disease. The lack of benefit shown in the largest fetal cell transplant trial to date, the Multicenter Intracerebral Transplant in Huntington's Disease (MIG‐HD), cautions against uncontrolled cell therapy treatments. However, MIG‐HD resulted in new procedures which significantly improved patient safety and enlightened upcoming cell transplant protocols. Stem cells should dramatically change the landscape by permitting better control of the quantity and homogeneity of the donor cell product. Here, we propose ways to improve future trials, thereby increasing their chance for success.
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