ORALLY BIOAVAILABLE SMALL MOLECULE SPLICING MODIFIERS WITH SYSTEMIC AND EVEN HTT-LOWERING ACTIVITY IN VITRO AND IN VIVO

BackgroundHuntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). Consequently, the mutant protein is ubiquitously expressed and drives HD pathogenesis via a toxic gain-of-function mechanism.1–3 HD animal models demonstrate that reducing huntingtin protein (HTT) levels alleviates motor and neuropathological abnormalities, supporting HTT lowering as a therapeutic approach2. Clinical and preclinical stage modalities including antisense oligonucleotides, virally delivered microRNAs, and zinc finger transcription factors, reduce HTT levels by repressing HTT transcription, stability and/or translation.1 2 Such modalities require invasive procedures to reach the central nervous system (CNS) and are not evenly distributed. These compounds act via a novel mechanism promoting the inclusion of a pseudoexon containing a premature termination codon, leading to HTT messenger RNA (mRNA) degradation and reduction of HTT levels.AimsWe aimed to develop a class of small molecule splicing modifiers specifically synthesised to promote selective splicing and ultimately reduction in huntingtin mRNA and protein levels.Methods/TechniquesHere, we describe the identification of small molecule splicing modifiers lowering HTT expression by selective modulation of the critical recognition step of pre-mRNA splicing.Results/OutcomeThese data demonstrate the potential of small molecules that effectively lower HTT consistently throughout the CNS and periphery to be a non-invasive effective treatment option for patients.ConclusionsThis work represents the first example of the identification and optimisation of orally bioavailable splicing modifiers that penetrate all tissues and lower HTT evenly throughout the body.ReferencesWild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in huntington’s disease. Lancet Neurol 2017;16:837–847. Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in huntington’s disease. Neuron 2019;101:801–819. Nopoulos PC. Huntington disease: a single-gene degenerative disorder of the striatum. Dialogues Clin Neurosci 2016;18:91–98.