title: Antisense oligonucleotide mediated therapy of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA results from deletions or mutations ofsurvival motor neuron 1(SMN1), an essential gene.SMN2, a nearly identical copy, can compensate forSMN1loss ifSMN2exon 7 skipping is prevented. Among the many cis-elements involved in the splicing regulation ofSMNexon 7, intronic splicing silencer N1 (ISS-N1) has emerged as the most effective target for an antisense oligonucleotide (ASO)-mediated splicing correction ofSMN2exon 7. Blocking of ISS-N1 by an ASO has been shown to fully restoreSMN2exon 7 inclusion in SMA patient cells as well as in vivo. Here we review how ISS-N1 targeting ASOs that use different chemistries respond differently in the various SMA mouse models. We also compare other ASO-based strategies for therapeutic splicing correction in SMA. Given that substantial progress on ASO-based strategies to promoteSMN2exon 7 inclusion in SMA has been made, and that similar approaches in a growing number of genetic diseases are possible, this report has wide implications.
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine (2034 Vet Med Bld.), Iowa State University, Ames, IA 50011.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Sivanesan
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Howell
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Didonato
authors.forename: Ravindra N
authors.initials: RN
authors.lastname: Singh
keywords: ASO; Antisense oligonucleotide; ISS-N1; MOE; PMO; SMA; SMN; splicing