Stereopure Oligonucleotides for the Selective Silencing of Mutant Huntingtin (4703)

Objective: To present evidence from preclinical studies that stereopure oligonucleotides promote selective silencing of mutant HTT (mHTT) through a single nucleotide polymorphism (SNP). Background: Huntington’s disease (HD) is caused by CAG-repeat expansion (≥36 repeats) in the HTT gene that produces mHTT protein. The wild-type HTT protein is important for normal neuronal homeostasis and survival, so its suppression may have detrimental long-term consequences. Oligonucleotides that target the mutant variant of a heterozygous SNP in HTT can elicit selective activity by promoting RNase H-mediated degradation of mHTT transcripts. Wave Life Sciences’ oligonucleotides are designed using PRISMTM, our discovery and drug development platform, which combines our growing knowledge of how the interplay among oligonucleotide sequence, chemistry, and backbone stereochemistry impacts key pharmacologic properties. Design/Methods: Biochemical RNase H experiments were performed with synthetic mHTT and wtHTT RNA substrates, stereopure oligonucleotides and purified catalytic domain from RNase H1. Oligonucleotides were delivered to cultured, patient-derived iCell neurons (heterozygous and homozygous) under free-uptake conditions. In vivo efficacy and distribution studies were performed in BACHD transgenic mice carrying the human HTT gene with a repeat expansion and SNP of interest. Results: In biochemical experiments, Wave’s stereopure compounds degrade mHTT while largely sparing wtHTT RNA. In iCell neurons homozygous for the SNP, Wave’s stereopure oligonucleotides appear to be more potent than an analog of RG6042, a pan-silencing oligonucleotide in clinical testing for HD treatment for another sponsor. In heterozygous iCell neurons, Wave’s oligonucleotides promote preferential degradation of mHTT RNA, whereas the RG6042 analog decreases both mHTT and wtHTT transcripts. In BACHD mice, stereopure oligonucleotides engage mHTT RNA and lead to durable knockdown of mHTT in the cortex and striatum. Conclusions: In preclinical studies, Wave’s stereopure oligonucleotides targeting a heterozygous SNP in HTT lead to selective and durable knockdown of mHTT. Disclosure: Dr. Dale has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd.Dr. Frank-Kamenetsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Taborn has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Aklilu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Berkovitch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Brown has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Kandasamy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Kumarasamy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Mathieu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Iwamoto has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Yin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Yang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Standley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Favaloro has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Longo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd. Dr. Byrne has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SPARK: Biogen. Dr. Vargeese has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Wave Life Sciences Ltd.