Spinal muscular atrophy (SMA) is caused bymutations 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. Quinazolines increaseSMN2 promoter activityandinhibit the ribonucleic acid scavenger enzymeDcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMAmice. Here, we show that RG3039 distributed to central nervous systemtissues where it robustly inhibited DcpS enzymeactivity, but minimally activated SMNexpression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treatedSMAmice 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.
ASJC Scopus subject areas
- Molecular Biology