Grants and Contracts Details
Description
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.
Status | Active |
---|---|
Effective start/end date | 6/1/21 → 5/31/25 |
Funding
- CHDI Foundation: $675,876.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.