title: Analysis of a read-through promoting compound in a severe mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is the leading genetic cause of infantile death and caused by the loss of functional Survival Motor Neuron 1 (SMN1). The remaining copy gene, SMN2, is unable to rescue from disease because the primary gene product lacks the final coding exon, exon 7, due to an alternative splicing event. While SMNΔ7 is a rapidly degraded protein, exon 7 is not specifically required in a sequence-specific manner to confer increased functionality to this truncated protein. Based upon this molecular observation, aminoglycosides have been examined to artificially elongate the C-terminus of SMNΔ7 by "read-through" of the stop codon. An SMNΔ7 read-through event benefits intermediate mouse models of SMA. Here we demonstrate that delivery of a read-through inducing compound directly to the CNS can partially lessen the severity of a severe model of SMA (Smn(-/-); SMN2(+/+)), albeit not to the extent seen in the less severe model. This further demonstrates the utility of read-through inducing compounds in SMA.
authors: Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA. mattisv@cshs.org
authors: Virginia B
authors: VB
authors: Mattis
authors: Cheng-Wei
authors: CW
authors: Tom Chang
authors: Christian L
authors: CL
authors: Lorson
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D018388:Codon, Terminator; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000187:drug effects; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D019076:Transgenes
chemical_list: D000617:Aminoglycosides; D018388:Codon, Terminator; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; C546326:TC007