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Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy
Kevin A. Kaifer ... D.D.W. Cornelison, Christian L. Lorson
Kevin A. Kaifer ... D.D.W. Cornelison, Christian L. Lorson
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e89970. doi:10.1172/jci.insight.89970.
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Categories: Research Article Neuroscience Therapeutics

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 called SMN2; however, the majority of SMN2-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-PLS3 extends 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. PLS3 coadministration improves the phenotype beyond the ASO, demonstrating the potential utility of combinatorial therapeutics in SMA that target SMN-independent and SMN-dependent pathways.

Authors

Kevin A. Kaifer, Eric Villalón, Erkan Y. Osman, Jacqueline J. Glascock, Laura L. Arnold, D.D.W. Cornelison, Christian L. Lorson

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