Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to thefunctional lossof theSMN1geneandtheinabilityof itsparalog,SMN2, tofullycompensateduetoreducedexon 7 splicing efficiency. SinceSMA patients have at least one copy ofSMN2, drug discovery campaigns have sought to identifySMN2inducers.C5-substituted quinazolines increaseSMN2promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varyingdiseaseseverity (Taiwanese 5058Hemiand2B/2SMAmice), andpositively impact sneuromuscular pathologies. In 2B/2 SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosingbegan atP4, highlightingthe importanceof early intervention.We determinedthe minimumeffective dose and the associated pharmacokinetic (PK) and exposure relationship ofRG3039 and DcpS inhibition ex vivo. These data support the long PKhalf-life with extended pharmacodynamic outcome of RG3039 in 2B/2 SMA mice. Inmotorneurons,RG 3039 significantly increased both theaverage number of cell swithgemsandaveragenumber of gems per cell, which is used as an indirectmeasure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.
ASJC Scopus subject areas
- Molecular Biology