This technology includes the identification and use of antisense oligonuclecotides (ASOs) complimentary to the 5’UTR of SMN2 (Survival of motor neuron 2) for the treatment of spinal muscular atrophy (SMA). SMA is an autosomal-recessive motor neuron disease caused by the loss of both copies of the SMN1 gene. Copies of the similar gene SMN2 decrease the severity of this disease in a dose-dependent manner. Thus, increasing expression levels of the SMN2 transcript can be used to treat SMA. We found that targeting the 5' end with an ASO significantly increases SMN2 mRNA levels, but not pre-mRNA levels, suggesting the use of these ASO offers protection to mature transcripts.
Splice-switching oligonucleotides, such as nusinersen, have been successfully used to increase full-length SMN levels, but their effects have a ceiling, which is determined by the abundance of total SMN2 transcripts in the cell. The 5'UTR ASO overcomes this "ceiling effect" because it increases total SMN transcript levels. Combining the 5’UTR ASO with the splice-switching oligonucleotide increases SMN protein levels more than using the splicing oligonucleotide alone.