title: Oligonucleotide-mediated survival of motor neuron protein expression in CNS improves phenotype in a mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is caused by homozygous mutation or deletion of the SMN1 gene encoding survival of motor neuron (SMN) protein, resulting in the selective loss of alpha-motor neurons. Humans typically have one or more copies of the SMN2 gene, the coding region of which is nearly identical to SMN1, except that a point mutation causes splicing out of exon 7 and production of a largely nonfunctional SMNDelta7 protein. The development of drugs that mitigate aberrant SMN2 splicing is an attractive therapeutic approach for SMA. A steric block antisense oligonucleotide (AO) has recently been developed that blocked an intronic splice suppressor element, and enhanced SMN2 exon 7 inclusion in SMA patient fibroblasts. Here, we show that periodic intracerebroventricular (ICV) delivery of this AO resulted in increased SMN expression in brain and spinal cord to as much as 50% of the level of healthy littermates. Real-time PCR of SMN2 transcripts confirmed the AO-mediated increase in full-length SMN. The AO-derived increase in SMN expression led to a concomitant improvement in bodyweight throughout the lifespan of the SMA animals. Treatment of SMA mice with AO also provided partial correction of motor deficits, manifest as improved righting response. Injections of a scrambled oligonucleotide had no effect on SMN expression or phenotype in the SMA mice. Our results validate that AOs that abrogate aberrant splicing of SMN2 are promising compounds for treating SMA.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Williams
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Schray
authors.forename: Carlyn A
authors.initials: CA
authors.lastname: Patterson
authors.forename: Semira O
authors.initials: SO
authors.lastname: Ayitey
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Tallent
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lutz
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007276:Injections, Intraventricular / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016376:Oligonucleotides, Antisense; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein