Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model.
Increasing survival of motor neuron 2, centromeric (SMN2) exon 7 inclusion to express more full-length SMN protein in motor neurons is a promising approach to treat spinal muscular atrophy (SMA), a genetic neurodegenerative disease. Previously, we identified a potent 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified antisense oligonucleotide (ASO) that blocks an SMN2 intronic splicing silencer element and efficiently promotes exon 7 inclusion in transgenic mouse peripheral tissues after systemic administration. Here we address its efficacy in the spinal cord--a prerequisite for disease treatment--and its ability to rescue a mild SMA mouse model that develops tail and ear necrosis, resembling the distal tissue necrosis reported in some SMA infants. Using a micro-osmotic pump, we directly infused the ASO into a lateral cerebral ventricle in adult mice expressing a human SMN2 transgene; the ASO gave a robust and long-lasting increase in SMN2 exon 7 inclusion measured at both the mRNA and protein levels in spinal cord motor neurons. A single embryonic or neonatal intracerebroventricular ASO injection strikingly rescued the tail and ear necrosis in SMA mice. We conclude that this MOE ASO is a promising drug candidate for SMA therapy, and, more generally, that ASOs can be used to efficiently redirect alternative splicing of target genes in the CNS.
Hua
Yimin
Y
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Sahashi
Kentaro
K
Hung
Gene
G
Rigo
Frank
F
Passini
Marco A
MA
Bennett
C Frank
CF
Krainer
Adrian R
AR
D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects*; D009134:Muscular Atrophy, Spinal / Q000503:physiopathology / Q000628:therapy; D009336:Necrosis / Q000188:drug therapy / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D016376:Oligonucleotides, Antisense; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein