Abstract Details

Title Evaluation of a Small Molecule Genetic Medicine RTX-317 in Preclinical Models of Huntington's Disease

Topic Movement Disorders

Presentation(s) P10 - Poster Session 10 (5:00 PM-6:00 PM)

Poster/Presentation
Number 5-010

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.

Authors/Disclosures
Sridhar Narayan, PhD PRESENTER	Dr. Narayan has received personal compensation for serving as an employee of ReviR Therapeutics.
Mary McMahon, PhD	Dr. McMahon has received personal compensation for serving as an employee of ReviR Therapeutics .
Jawad Abid	Mr. Abid has nothing to disclose.
Shilin Chen (ReviR Therapeutics)	No disclosure on file
Jiacheng Zhang, PhD	Dr. Zhang has nothing to disclose.
Kendra Lew (ReviR Therapeutics)	No disclosure on file
Jacqueline Salotti, PhD	Dr. Salotti has received personal compensation for serving as an employee of ReviR Therapeutics.
Xing Tang (ReviR Therapeutics)	No disclosure on file
Steve Lianoglou, PhD	Mr. Lianoglou has received personal compensation for serving as an employee of ReviR Therapeutics.
Jinxing Li, PhD	Dr. Li has nothing to disclose.
Yang Liu (ReviR Therapeutics)	No disclosure on file
Paul R. August, PhD	Dr. August has received personal compensation for serving as an employee of ReviR Therapeutics. Dr. August has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Charcot Marie Tooth Research Foundation. Dr. August has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for AcuraStem. Dr. August has stock in Acurastem. Dr. August has stock in ReviR Therapeutics. The institution of Dr. August has received research support from CMTRF.

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