Antisense oligonucleotides to treat spinal muscular atrophy
The loss of a single gene causes spinal muscular atrophy, a devastating disease that is among the leading genetic causes of infant death. This missing gene, called survival motor neuron 1 (SMN1), is nearly identical to a “copy” gene called SMN2. The primary difference between these two genes exists at the pre-mRNA processing level: SMN1 produces exclusively full-length transcripts, whereas SMN2 produces low levels of full-length SMN (approximately 10% compared to SMN1-derived levels) and an abundance of an alternatively spliced truncated isoform lacking the final coding exon (exon 7).
The differential splicing pattern is due to a single, silent nucleotide difference between SMN1 and SMN2. Importantly, however, all SMA patients retain one or more copies of SMN2 and the low level of SMN2-derived SMN protein is fully functional. Therefore, SMN2 has been envisioned as an ideal therapeutic target, particularly for those strategies that could modulate the SMN2 splicing pattern and generate more full-length SMN.
We have previously characterized a genetic region upstream of SMN2 exon 7 called Element 1 (E1) that functions as a repressor of SMN2 exon 7 inclusion. The presence of this genetic element reduces the production of the full-length SMN product by promoting the exclusion of exon 7 and the expression of the truncated isoform (SMN-delta7). Molecules that block or inhibit the repressive activity of E1 could be envisioned as potential therapies for SMA is they relieve the repression and allow for high levels of full-length SMN expression from the SMN2 gene. To this end, we have developed an antisense oligonucleotide that anneals to the E1 region using the well-characterized Morpholino chemistry for the molecules’ backbone.