Neural transplants not an effective therapy for Huntington's Disease

24 July 2009

Huntington’s disease (HD) is a rare inherited autosomal dominant disorder cause by increased CAG repeats in the huntingtin gene leading to the production of mutant huntingtin protein. The accumulation of this mutant protein within the brain leads to selective loss of neurons in certain regions of the brain, most notably in the striatum. Neurodegeneration causes progressive cognitive and motor deficits that manifest most commonly between the ages of 35 and 44 years and is ultimately fatal. Although treatments are available to combat the psychiatric symptoms associated with this disease, there is no effective treatment to combat neuronal loss.

One possible method of inducing brain repair is through neural transplantation (i.e. grafting of healthy neural tissue in order to repopulate lost neurons), which was suggested as a possible treatment for HD in the 1990s following a number of experiments in rodents and primates which demonstrated the feasibility of this approach. These studies showed that embryonic striatal grafts were able to survive, induce behavioural recovery and establish connectivity in rodent brains. Several programs evaluating the safety, tolerability and potential efficacy of neural transplants were initiated and preliminary studies of neural transplants in patients with HD demonstrated 2-4 years of modest clinical benefits. However, this was followed by clinical deteriorations similar to the natural course of the disease.

In a paper published in the Proceedings of the National Academy of Science this week, Cicchetti et al. have analysed the brains of three people with HD who received fetal striatal-tissue transplants a decade before they died in order to determine why the transplants were not effective for longer [Cicchetti et al (2009) PNAS doi:10.1073/pnas.0904239106]. The brains were examined for the presence of the grafts, markers of projection neurons, abnormal huntingtin protein deposits and inflammatory cells. The study identified that loss of clinical benefit was due to damage and loss of the grafts, which had undergone disease-like neuronal degeneration even though they did not possess the genetic mutation causing HD. Previous studies had reported healthy graft survival at 18 months and 6 years post-tranplantation, suggesting that over the long-term graft survival is attenuated. This is thought to be as a result of the toxic environment to which the grafts were exposed, which itself is thought to be the mechanism by which neuronal loss of the host tissue occurs.

The authors conclude that future trials of fetal-cell transplantation are probably unwarranted, as the risks of the procedure and the disease-like graft degeneration outweigh its benefits, which are short term and mild. They suggest a better approach would be strategies aimed at altering the inflammatory or immune responses, host-derived neurotoxicity, and providing neurotrophic support in order to encourage growth and differentiation of new neurons and survival of existing ones, all of which may still be based on neurotransplantation.

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