title: Trans-splicing-mediated improvement in a severe mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy is a leading genetic cause of infantile death and occurs in approximately 1/6000 live births. SMA is caused by the loss of Survival Motor Neuron-1 (SMN1), however, all patients retain at least one copy of a nearly identical gene called SMN2. While SMN2 and SMN1 are comprised of identical coding sequences, the majority of SMN2 transcripts are alternatively spliced, encoding a truncated protein that is unstable and nonfunctional. Considerable effort has focused upon modulating the SMN2 alternative splicing event since this would produce more wild-type protein. Recently we reported the development of an optimized trans-splicing system that involved the coexpression of a SMN2 trans-splicing RNA and an antisense RNA that blocks a downstream splice site in SMN2 pre-mRNA. Here, we demonstrate that in vivo delivery of the optimized trans-splicing vector increases an important SMN-dependent activity, snRNP assembly, in disease-relevant tissue in the SMA mouse model. A single injection of the vector into the intracerebral-ventricular space in SMA neonates also lessens the severity of the SMA phenotype in a severe SMA mouse model, extending survival approximately 70%. Collectively, these results provide the first in vivo demonstration that SMN2 trans-splicing leads to a lessening of the severity of the SMA phenotype and provide evidence for the power of this strategy for reprogramming genetic diseases at the pre-mRNA level.
authors.affiliation: Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Tristan H
authors.initials: TH
authors.lastname: Coady
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D007276:Injections, Intraventricular; D051379:Mice; D018345:Mice, Knockout; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D012720:Severity of Illness Index; D055533:Survival of Motor Neuron 1 Protein / Q000008:administration & dosage / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000008:administration & dosage / Q000235:genetics; D020040:Trans-Splicing / Q000235:genetics / Q000502:physiology*
chemical_list: C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein