Abstract
Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.
Highlights
Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene
Intron predictions from the gapped alignments show that branaplam promotes the splicing-in of previously unannotated pseudoexons between annotated exons, as exemplified for the Ellis-van Creveld (EVC) gene (Fig. 1a)
Genome-wide, 100 nM branaplam promotes the inclusion of 94 unannotated pseudoexons that map to GENCODE genes and show a fold change >2 with an multiple testing correction (MTC)-adjusted P value < 0.01 (Fig. 1b and Supplementary Table 2)
Summary
Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. HTT lowering using ASOs, siRNAs or miRNAs in different mouse models reduces mutant HTT (mHTT) in the brain with significant improvements in motor and behavioral deficits[4–9] In the clinic, these therapies require either surgical delivery of a viral vector for chronic HTTtranscript lowering by RNAi, or repeated infusions into the CSF by lumbar puncture for ASOs. NVS-SM1 (LMI070), called branaplam, is a pyridazine derivative with broad CNS and systemic distribution[10]. NVS-SM1 (LMI070), called branaplam, is a pyridazine derivative with broad CNS and systemic distribution[10] It was initially developed as a therapeutic for children with spinal muscular atrophy (SMA) as it modulates splicing of the poorlyspliced survival motor neuron 2 (SMN2) gene and restores fulllength SMN2 transcript and SMN protein levels to normal[10]. We show through a series of in vitro, in vivo, and ex vivo human blood sample analyses, that recognition of the non-canonical nGA 3’-exonic motif by branaplam promotes the inclusion of a pseudoexon in human HTT transcripts, causing downregulation of HTT mRNAs and protein
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