Huntingtin lowering therapeutics

The premise in study of Huntington's disease (HD) is that the gene mutation—expansion of the CAG repeats in the huntingtin gene—is fundamental to the pathogenesis of the disease. How the gene mutation causes HD is not established; two processes have established primacy to contribute to premature neuronal dysfunction and death. First is the inherited CAG repeat expansion itself. The mode for inherited CAG repeats expansions is 42 (Snell et al., 1993). The longer the repeat is, the earlier is the onset of disease, until about 60 repeats at which the onset is in the juvenile age group. Second is the realization that the CAG expansion is unstable. Somatic expansion of the CAG repeat was described early in studies on mutant HTT in brain (Aronin et al., 1995). This phenomenon was confirmed by additional studies (Kennedy & Shelbourne, 2000; Kennedy et al., 2003). Subsequent mouse and GWAS studies link mismatch repair to both somatic expansion and disease (Chapters 2–4Chapter 2Chapter 3Chapter 4).