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Colin Watts and Stephen B. Dunnett

Object. The goal of this study was to investigate the effect of the severity of host neural damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease.

Methods. Sprague—Dawley rats were subjected to unilateral striatal lesioning induced by administration of quinolinic acid (20 nM, 40 nM, or 90 nM). Seven days postlesioning, intrastriatal cell suspension grafts were placed in the right striatum in some of these animals. Grafts were also placed in the right striatum of additional animals that had not been subjected to lesioning. The rats were killed and processed for morphological analysis 8 weeks after grafting.

The results indicate that striatal grafts survive and grow much better when implanted into a lesioned striatum rather than into an intact striatum, as measured both by the volume and the numbers of medium-sized spiny neurons within the graft. Only a small or modest lesion is necessary to produce this effect. By some measures (such as graft volume) grafts survive less well when the lesion is more extensive. The presence of a graft reduced the extent of striatal atrophy induced by the lesions, but this effect was not caused by differences in the numbers of surviving neurons per se.

Conclusions. These results have significant implications for the timing of surgical intervention and patient selection with respect to current and future clinical trials of striatal transplantation in the treatment of Huntington's disease.

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Claire D. Clelland, Roger A. Barker and Colin Watts

✓ Huntington disease (HD), caused by polyglutamate expansions in the huntingtin protein, is a progressive neurodegenerative disease resulting in cognitive and motor impairments and death. Neuronal dysfunction and degeneration contribute to progressive physiological, motor, cognitive, and emotional disturbances characteristic of HD. A major impetus for research into the treatment of HD has centered on cell therapy strategies to protect vulnerable neuronal cell populations or to replace dysfunctional or dying cells. The work underlying 3 approaches to HD cell therapy includes the potential for self-repair through the manipulation of endogenous stem cells and/or neurogenesis, the use of fetal or stem cell transplantation as a cell replacement strategy, and the administration of neurotrophic factors to protect susceptible neuronal populations. These approaches have shown some promising results in animal models of HD. Although striatal transplantation of fetal-derived cells has undergone clinical assessment since the 1990s, many cell therapy strategies have yet to be applied in the clinic environment. A more thorough understanding of the pathophysiologies underlying HD as well as the response of both endogenous and exogenous cells to the degenerating brain will inform their merit as potential therapeutic agents and enhance the framework by which the success of such strategies are determined.