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 differential splicing pattern of the two genes 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. We have developed and tested (both in vitro and in vivo) a number of anti-sense oligionucleotides that anneal to this region using the well-characterized Morpholino chemistry for the molecules’ backbone. One compound (Ev1.11) has shown tremendous efficacy benefits versus controls in transgenic mice, as well as previously published molecules by other groups. Additionally, we have performed initial ADME and Toxicity assays on this compounds which show great clinical potential. In 2019, we are conducing GLP animal studies in order to file an IND with the FDA in 2020.