Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene, and insufficient expression of full-length survival motor neuron (SMN) protein. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter 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. The pharmacological characterisation of RG3039, reported in two new studies in Human Molecule Genetics, demonstrates that RG3039 can extend survival, improve function, and impact neuromuscular pathology in three SMA mouse models of varying disease severity.
In the first paper, by Dr. DiDonato et al., report the results obtained in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/- SMA mice). In 2B/- SMA mice, RG3039 provides >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. They determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex-vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/- SMA mice. In motor neurons, RG3039 significantly increased the number of gems and cells with gems, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.
The second paper by Dr. Sumner et al., shows that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight, and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically-restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy.