Advancing HD therapeutics

The National Institute of Neurological Disorders and Stroke awarded a cooperative agreement of $1,038,135 to the University of Massachusetts Medical School on September 2, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The award funds research to develop and optimize a trivalent small interfering RNA (siRNA) therapeutic targeting Huntington's disease pathogenesis. The investigative approach employs multiple simultaneously delivered siRNAs to block three disease-driving processes: full-length mutant huntingtin protein expression, somatic expansion of CAG trinucleotide repeats via MSH3 inhibition, and production of the toxic huntingtin exon 1 protein. Preliminary data demonstrate that silencing these targets reduces mutant huntingtin protein in brain tissue including the neostriatum, halts somatic repeat expansion, and improves molecular signatures in HD model mice. The trivalent siRNA maintains long-term RNA interference bioactivity for at least three months and distributes throughout the brain, including deep structures. The award supports optimization of the siRNA structure in UG3 format and chemistry, manufacturing, and controls synthesis, with intent to support an eventual FDA application for HD patient treatment in a UH3 phase.

Performance occurs in Worcester, Massachusetts, from September 2, 2026, through August 31, 2028. The cooperative agreement is assistance type funding through NIH NINDS.

Abstract

Abstract huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disease. Despite its straightforward genetic basis, HD has a complex pathogenesis. No FDA approved treatment exists. IT is now recognized that multiple processes interact to shorten neuronal survival in the neostriatum, and eventually throughout the brain. Three processes contribute to HD: the inheritance of more than 35 CAG trinucleotide CAG repeats in the huntingtin gene, somatic expansion of these inherited repeats over time to yield overt 180 CAG repeats in series, and aberrant splicing of the mutant huntingtin gene to create a shortened, exon 1 generated protein that is thought to have high pathogenicity. This proposal will employ an innovative application of RNA interference by using multiple simultaneously delivered sirnas, in a single scaffold, to block all three processes of HD and demonstrate safety and effectiveness. The small interfering rnas have a new structure that will be optimized in the UG3 format and then organized to apply to the FDA for eventual treatment of HD patients in the UH3. Preliminary data demonstrate silencing of full-length mutant huntingtin to substantially reduce the protein in the brain, including the neostriatum; the mismatch repair protein MSH3, to stop the somatic expansion of CAG repeats in the huntingtin protein; and MHTT1A, the putative toxic huntingtin exon 1 protein of mutant huntingtin, under the regulation of polya in intron 1. We show that silencing these proteins improves the molecular signature found in HD model mice. The three sirnas are delivered in a novel trivalent sirna, with long-term rnai bioactivity over at least three months and the potential to stop the HD pathogenic process. The trivalent distributes throughout the brain, including deep brain structures such as the neostriatum (so far, mice and sheep). We show CMC (chemistry, manufacturing, controls) synthesis of the novel trivalent sirna and present safety data assuring its go-no-go quality. We will test the trivalent sirna in HD model mice and minipig in the UG3 (recommended by the FDA), and in non-human primate in the UH3. The goal is to present an IND to the FDA for the treatment of HD.