Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by survival motor neuron (SMN) protein deficiency which results in motor neuron loss and muscle atrophy. SMA is caused by a mutation or deletion of the survival motor neuron 1 (SMN1) gene and retention of the nearly identical SMN2 gene. SMN2 contains a C to T change in exon 7 that results in exon 7 exclusion from 90% of transcripts. SMN protein lacking exon 7 is unstable and rapidly degraded. The remaining full-length transcripts from SMN2 are insufficient for normal motor neuron function leading to the development of SMA. Three different therapeutic approaches that increase full-length SMN (FL-SMN) protein production are approved for treatment of SMA patients. Studies in both animal models and humans have demonstrated increasing SMN levels prior to onset of symptoms provides the greatest therapeutic benefit. Treatment of SMA, after some motor neuron loss has occurred, is also effective but to a lesser degree. The SMN∆7 mouse model is a well characterized model of severe or type 1 SMA, dying at 14 days of age. Here we treated three groups of ∆7SMA mice starting before, roughly during, and after symptom onset to determine if combining two mechanistically distinct SMN inducing therapies could improve the therapeutic outcome both before and after motor neuron loss. We found, compared with individual therapies, that morpholino antisense oligonucleotide (ASO) directed against ISS-N1 combined with the small molecule compound RG7800 significantly increased FL-SMN transcript and protein production resulting in improved survival and weight of ∆7SMA mice. Moreover, when give late symptomatically, motor unit function was completely rescued with no loss in function at 100 days of age in the dual treatment group. We have therefore shown that this dual therapeutic approach successfully increases SMN protein and rescues motor function in symptomatic ∆7SMA mice.