• Huntington disease
• fetal striatal transplantation

In this issue of the Journal (pp 678–685),¹ the NEST-UK consortium reports safety data on four subjects with Huntington's disease receiving unilateral intrastriatal transplantation of human fetal striatal tissue. This well designed and carefully executed study adds to the small amount of previous data on fetal striatal grafting for Huntington's disease.^2,3,4 Groups in California and France reported a total of eight subjects receiving bilateral engraftment without complications and either no change in clinical outcome measures or some improvement.^2,3 In another series of seven patients undergoing bilateral engraftment, there were four subdural haematomas (in three subjects), two requiring neurosurgical drainage.⁴ These latter subjects may have had more advanced Huntington's disease with a greater degree of brain atrophy, and this may be a contraindication to engraftment. The NEST-UK investigators plan a second phase safety study examining bilateral engraftment with a total of 10 subjects (including the four in the present report), and a two year follow up to generate preliminary efficacy data. This systematic approach is commendable.

The accumulated data, however, raise real questions about moving forward into efficacy trials. An incidence of two symptomatic subdural haematomas among 19 subjects is unacceptable. It is imperative that efficacy trials be controlled appropriately. The recent experience with fetal tissue engraftment for Parkinson disease revealed the existence of large magnitude and remarkably long duration placebo effects. Some form of sham surgery control is necessary. The NEST-UK protocol involves general anaesthesia, the surgery, a week of postoperative hospital care, and immunosuppression with frequent blood monitoring. Designing an adequate and safe sham surgery protocol will be a challenge.

The rationale for the fetal striatal transplantation is questionable. Successful striatal engraftment is likely to have limited effects. The hallmark of Huntington's disease is striatal degeneration, but the disorder affects the whole brain. There is significant whole brain atrophy, and neurodegeneration of the neocortex, hippocampal formation, thalamus, substantia nigra, and cerebellum have all been documented. Fetal striatal transplantation has shown efficacy in animal models of Huntington's disease, but these models use mainly toxin destruction of the striatum and do not mimic the systemic nature of Huntington's disease. If there were no alternative approaches, continued pursuit of engraftment would be rational. However, identification of the genetic defect in Huntington's disease—expanded CAG repeats within the huntingtin locus—resulted in an explosion of research on the pathogenesis of the disease. Recent advances include the development of several murine genetic models and the identification of various molecular processes as potential therapeutic targets. I believe the likelihood of an effective treatment emerging from these lines of investigation is considerably higher than the likelihood of marked improvement with fetal striatal engraftment.

Given the practical and theoretical objections to fetal striatal engraftment for Huntington's disease, the best approach would be for the NEST-UK investigators and other groups in this area to complete their safety trials and then pause.