Oligonucleotide-Mediated Survival of Motor Neuron Protein Expression in CNS Improves Phenotype in a Mouse Model of Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is caused by homozygous mutation or deletion of the <i>SMN1</i> gene encoding survival of motor neuron (SMN) protein, resulting in the selective loss of α-motor neurons. Humans typically have one or more copies of the <i>SMN2</i> gene, the coding region of which is nearly identical to <i>SMN1</i>, except that a point mutation causes splicing out of exon 7 and production of a largely nonfunctional SMNΔ7 protein. The development of drugs that mitigate aberrant <i>SMN2</i> splicing is an attractive therapeutic approach for SMA. A steric block antisense oligonucleotide (AO) has recently been developed that blocked an intronic splice suppressor element, and enhanced <i>SMN2</i> exon 7 inclusion in SMA patient fibroblasts. Here, we show that periodic intracerebroventricular (ICV) delivery of this AO resulted in increased SMN expression in brain and spinal cord to as much as 50% of the level of healthy littermates. Real-time PCR of <i>SMN2</i> transcripts confirmed the AO-mediated increase in full-length SMN. The AO-derived increase in SMN expression led to a concomitant improvement in bodyweight throughout the lifespan of the SMA animals. Treatment of SMA mice with AO also provided partial correction of motor deficits, manifest as improved righting response. Injections of a scrambled oligonucleotide had no effect on SMN expression or phenotype in the SMA mice. Our results validate that AOs that abrogate aberrant splicing of <i>SMN2</i> are promising compounds for treating SMA.