title: The DcpS inhibitor RG3039 improves motor function in SMA mice.
abstract: 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.
authors.affiliation: These authors contributed equally to this study.
authors.forename: James P
authors.initials: JP
authors.lastname: Van Meerbeke
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Gibbs
authors.forename: Heather L
authors.initials: HL
authors.lastname: Plasterer
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Feng
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Lin
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Rucki
authors.forename: Claribel D
authors.initials: CD
authors.lastname: Wee
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Shefali
authors.initials: S
authors.lastname: Sharma
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.forename: Darrick K
authors.initials: DK
authors.lastname: Li
authors.forename: Livio
authors.initials: L
authors.lastname: Pellizzoni
authors.forename: James R
authors.initials: JR
authors.lastname: Rusche
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Ko
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: C587914:5-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diamine; D011799:Quinazolines; D017411:Ribonucleoproteins, Small Nuclear; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D004722:Endoribonucleases; C508554:DcpS protein, mouse