Splicing of precursor messenger RNAs (pre-mRNAs) to mature messenger RNAs (mRNAs) is a prevalent mechanism and a key step by which the expression of most eukaryotic genes is regulated. The recent discovery of novel small molecules that target splicing events involved in the expression of the Survival of Motor Neuron 2 (SMN2) and Huntingtin (HTT) genes have led to promising therapeutic options for spinal muscular atrophy (SMA) and Huntington’s disease (HD).  In this presentation, I will describe our HTT-lowering program, which is part of PTC’s proprietary pre-mRNA splicing platform, where we leverage our knowledge of splicing regulation as a novel platform to discover and develop oral systemically distributed small-molecule splicing modifiers.  Utilizing this cutting-edge technology, we have identified small molecule splicing modifiers that cross the blood brain barrier upon oral delivery, and uniformly lower HTT levels in the key affected areas of an HD mouse brain.  The presentation will describe how these small molecules were identified and optimized for improved oral bioavailability, penetration of the blood-brain-barrier and potency. The discovery and development of such novel small molecules that modify splicing has expanded the scope of drug targets to include many previously considered “undruggable” genes that are implicated in various human disorders, including oncology and neurological diseases.

Therapeutic RNA splicing modulation – a blossoming landscape inspired by spinal muscular atrophy (SMA)

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.