Novel therapies in the search for a cure for Huntington's disease

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Abstract
The present era is one of tremendous excitement and rapid innovation in Huntington's disease (HD) research. The pace of research seems to be rapidly quickening. The discovery of the gene and the subsequent development of transgenic mouse models of HD have been major breakthroughs. Now, after a large number of experimental studies in animals, a few pilot clinical trials have been initiated. The work presented by Freeman et al. (1) in a recent issue of PNAS reports the survival and development of a graft, derived from human fetal striatal, in a patient with HD. The molecular basis of HD, and at least seven other diseases, that renders it amenable to potential gene therapy techniques involves the expansion of a CAG repeat in the genome, leading to the production of a mutant protein with an expanded polyglutamine repeat. It is now evident that changes in gene expression occur early in polyglutamine diseases, as early as 1 day after the initial expression of the mutant gene in animal models (2). Recent studies have demonstrated that huntingtin, as well as other polyglutamine-containing proteins, can directly interact with transcription factors. Of particular interest, the HD protein has been shown to directly interact with P53 and CREB-binding protein (CBP) (3). This interaction then represses transcription. In studies of cell culture and transgenic mouse models of spinal and bulbar muscular atrophy, it has been demonstrated that the CBP is incorporated into nuclear inclusions formed by polyglutamine-containing proteins and cultured cells (4). It is also found in intranuclear inclusions in tissue from patients with spinal and bulbar muscular atrophy. The CBP is also incorporated into nuclear inclusions found in a cell culture model of spinocerebellar ataxia type 3. Overexpression of CBP rescues cells from polyglutamine toxicity. CBP is an important transcriptional coactivator that orchestrates nuclear responses to …