Analysis of a read-through promoting compound in a severe mouse model of spinal muscular atrophy

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 SMN Delta 7 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 SMN Delta 7 by "read-through" of the stop codon. An SMN Delta 7 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(-/-); SMN+/+.), albeit not to the extent seen in the less severe model. This further demonstrates the utility of read-through inducing compounds in SMA. (c) 2012 Elsevier Ireland Ltd. All rights reserved.