From open to large-scale randomized cell transplantation trials in Huntington's disease: Lessons from the multicentric intracerebral grafting in Huntington's disease trial (MIG-HD) and previous pilot studies.

Fifty-one patients from open-label pilot trials have been transplanted in Huntington's disease (HD) using human fetal cells; clinical data and follow-up are available in 30 of them. These open-label studies were mostly designed for safety and feasibility. However, signs of long-term efficacy have been reported in 4 out of 30 patients, differences in tissue preparation, surgical procedure, patients characteristics, immunosuppression regimens, clinical, and imaging assessments, makes it difficult to define the optimal procedure for future trials. Forty-five patients have now been grafted in the multicentric intracerebral grafting trial in Huntington's in France (MIG-HD) and Belgium, and 22 in Germany in a randomized delayed start design. Whereas the 10 patients published from the German cohort showed no improvement, the results from the MIG-HD trial are still under analysis. However, the MIG-HD trial has already changed cell transplantation for HD by showing alloimmunization with graft rejection in one patient and HLA antibodies against the transplant in others. Moreover, MIG-HD has established a new surgical procedure to avoid subdural hematoma, the most frequent adverse effect in transplant in HD, and a surgical strategy to eradicate eventual choroid cysts. By reviewing all the published results, new avenues are provided for optimization for cell preparation, delivery methods, standardization of clinical assessment, and surgical procedure with blind video scoring, imaging, and electrophysiology. Future trials should capitalize on a new CAPIT-HD2 battery to determine efficacy with sufficiently long pre and postgraft follow-up, using patient stratification and randomization, control of alloimmunization, HLA monitoring, and standardization of the consent procedure.