Evaluation of a Small Molecule Genetic Medicine RTX-317 in Preclinical Models of Huntington's Disease
Sridhar Narayan1, Mary McMahon1, Jawad Abid1, Shilin Chen1, Jeff Zhang1, Kendra Lew1, Jacqueline Salotti1, Xing Tang1, Steve Lianoglou1, Jinxing Li1, Yang Liu1, Paul August1
1ReviR Therapeutics
Objective:
To evaluate the efficacy of RTX-317 in preclinical models of Huntington’s Disease
Background:
Huntington’s Disease (HD) is caused by a trinucleotide repeat expansion in the HTT gene that leads to aggregation of mutant huntingtin protein (mHTT) and degeneration of neurons in the striatum and other brain regions. Lowering mHTT mRNA and protein is a promising therapeutic strategy with several antisense oligonucleotides targeting mHTT currently in clinical trials. Targeting components of the mismatch repair pathway that has been identified as genetic modifiers of the disease, including PMS1, is emerging as a novel strategy to reduce somatic CAG repeat expansion in Huntington’s Disease. We have developed a number of mRNA splicing modulators that reduce both HTT and PMS1 mRNA levels by inducing the inclusion of poison exons within the pre-mRNAs leading to degradation by nonsense-mediated mRNA decay. Here, we discuss RTX-317 – an orally administered, brain penetrant, HTT and PMS1 lowering small molecule.
Design/Methods:
RTX-317 was evaluated in Huntington’s Disease models including patient primary cells and patient iPSC-derived medium spiny neurons. RTX-317 was also tested in vivo including in the BACHD mouse model of Huntington’s Disease.
Results:
We demonstrate the ability of RTX-317 to reduce the expression of mHTT and PMS1 in patient iPSC-derived cells including neural progenitors, cortical neurons, and medium spiny neurons. Differential analysis of gene expression highlights the selectivity of RTX-317 towards HTT and PMS1 mRNA lowering. RTX-317 shows CAG repeat expansion lowering in in vitro models and demonstrates high brain and CSF disposition after oral dosing which reduces mHTT protein in vivo in HD mouse models.
Conclusions:
We anticipate RTX-317 will fill an unmet need for safe, effective, and convenient treatment of Huntington’s Disease and we continue to advance it to IND-enabling studies.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.