The DcpS inhibitor RG3039 improves motor function in SMA mice

• Published in: Human molecular genetics 2013-10, Vol.22 (20), p.4074-4083
• Main Authors: Van Meerbeke, James P, Gibbs, Rebecca M, Plasterer, Heather L, Miao, Wenyan, Feng, Zhihua, Lin, Ming-Yi, Rucki, Agnieszka A, Wee, Claribel D, Xia, Bing, Sharma, Shefali, Jacques, Vincent, Li, Darrick K, Pellizzoni, Livio, Rusche, James R, Ko, Chien-Ping, Sumner, Charlotte J
• Format: Article
• Language: English
• Subjects: Animals; Antisense oligonucleotides; Central Nervous System - drug effects; Central Nervous System - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endoribonucleases - antagonists & inhibitors; Humans; Mice; Mice, Transgenic; Motor Neurons - drug effects; Motor Neurons - physiology; Muscles - drug effects; Muscles - metabolism; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - physiopathology; Neuromuscular Junction - drug effects; Neuromuscular Junction - physiology; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Ribonucleoproteins, Small Nuclear - metabolism; Survival of Motor Neuron 1 Protein - metabolism; Survival of Motor Neuron 2 Protein - genetics; Survival of Motor Neuron 2 Protein - metabolism; Synaptic Transmission
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt257

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. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. 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 SMA mice. Here, we show 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.