Tolerability of Wildtype Huntingtin Lowering by RNA Interference in the Cynomolgus Macaque Brain

Tolerability of wildtype huntingtin lowering by RNA interference in the cynomolgus macaque brain Project Summary / Abstract Most huntingtin-lowering treatments in development or clinical trials are not selective for the mutant allele, but also lower wildtype huntingtin expression. Treatment of the cortex as well as the striatum may be desirable for optimal efficacy of a huntingtin-lowering treatment for Huntington’s disease. However, lowering huntingtin in the cortex may affect underlying neurotransmitter systems and/or reduce the transport of trophic factors from the cortex to the striatum that are necessary for the survival and function of striatal neurons. It is unknown whether reduction of wildtype huntingtin in corticostriatal neurons/tract of the primate brain will adversely affect the survival and functioning of striatal neurons. The thalamus is also a potential therapeutic target, but reduction of huntingtin in the thalamus causes pathologic calcification in mice and it is unknown whether this might also occur in the primate brain. The purpose of this project is to fill critical gaps in our scientific knowledge about the effects of lowering huntingtin protein expression in the corticostriatal connections and the thalamus of the primate brain by quantitatively measuring the effects of this lowering in cynomolgus macaques administered MRI-guided injections of AAV6 encoding a huntingtin-lowering shRNA or a control shRNA, directly into either the striatum or thalamus. Monkeys will be assessed by periodic behavioral and neurological exams. In vivo glutamate signaling in the cortex, striatum and thalamus will be assessed 9 months after AAV administration. Post-mortem analysis will include assessments of dopamine turnover and BDNF levels in striatal tissue as well as calcium in the thalamus and neuropathological evaluations of coronal brain sections, including cortex, striatum and thalamus. The data obtained by this project in the nonhuman primate will provide information that cannot be readily obtained from human clinical trials of huntingtin-lowering treatments. This information will be pertinent to any current and future generations of huntingtin-lowering therapies for Huntington’s disease.