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      Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model.

      Genes & development

      Alternative Splicing, Animals, Animals, Newborn, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, drug effects, Male, Mice, Motor Neurons, Muscular Atrophy, Spinal, physiopathology, therapy, Necrosis, drug therapy, Oligonucleotides, Antisense, administration & dosage, pharmacokinetics, pharmacology, Spinal Cord, metabolism, Survival of Motor Neuron 2 Protein, genetics, Transgenes

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          Abstract

          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.

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          Author and article information

          Journal
          20624852
          2912561
          10.1101/gad.1941310

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