title: Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present calledSMN2; however, the majority ofSMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy. Several SMN-independent pathways that could impinge upon the SMA phenotype have been examined with varied success. To identify disease-modifying pathways that could serve as stand-alone therapeutic targets or could be used in combination with an SMN-inducing compound, we investigated adeno-associated virus-mediated (AAV-mediated) gene therapy using plastin-3 (PLS3). Here, we report that AAV9-PLS3extends survival in an intermediate model of SMA mice as well as in a pharmacologically induced model of SMA using a splice-switching ASO that increases SMN production.PLS3coadministration improves the phenotype beyond the ASO, demonstrating the potential utility of combinatorial therapeutics in SMA that target SMN-independent and SMN-dependent pathways.
authors.affiliation: Molecular Pathogeneses and Therapeutics Program.|Bond Life Sciences Center.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kaifer
authors.affiliation: Bond Life Sciences Center.|Department of Veterinary Pathobiology, College of Veterinary Medicine.
authors.forename: Eric
authors.initials: E
authors.lastname: Villalón
authors.affiliation: Bond Life Sciences Center.|Department of Veterinary Pathobiology, College of Veterinary Medicine.
authors.forename: Erkan Y
authors.initials: EY
authors.lastname: Osman
authors.affiliation: Molecular Pathogeneses and Therapeutics Program.
authors.forename: Jacqueline J
authors.initials: JJ
authors.lastname: Glascock
authors.affiliation: Division of Biological Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Arnold
authors.affiliation: Bond Life Sciences Center.|Division of Biological Sciences, University of Missouri, Columbia, Missouri, USA.
authors.forename: D D W
authors.initials: DDW
authors.lastname: Cornelison
authors.affiliation: Molecular Pathogeneses and Therapeutics Program.|Bond Life Sciences Center.|Department of Veterinary Pathobiology, College of Veterinary Medicine.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009046:Motor Neurons / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000473:pathology*; D016019:Survival Analysis; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C026742:plastin