The DcpS inhibitor RG3039 improves motor functionin SMA mice

James P. Van Meerbeke, Rebecca M. Gibbs, Heather L. Plasterer, Wenyan Miao, Zhihua Feng, Ming Yi Lin, Agnieszka A. Rucki, Claribel D. Wee, Bing Xia, Shefali Sharma, Vincent Jacques, Darrick K. Li, Livio Pellizzoni, James R. Rusche, Chien Ping Ko, Charlotte J. Sumner

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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.

Original languageEnglish (US)
Article numberddt257
Pages (from-to)4074-4083
Number of pages10
JournalHuman molecular genetics
Issue number20
StatePublished - Oct 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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