Abstract
Spinal muscular atrophy (SMA) is a major neurodegenerative disorder of children and infants. SMA is primarily caused by low levels of SMN protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1, fails to compensate for the loss of the production of the functional SMN protein due to predominant skipping of exon 7. Several compounds, including antisense oligonucleotides (ASOs) that elevate SMN protein from SMN2 hold the promise for treatment. An ASO-based drug currently under Phase III clinical trial employs intronic splicing silencer N1 (ISS-N1) as its target. Cumulative studies on ISS-N1 reveal a wealth of information with significance to the overall therapeutic development for SMA. Here, the authors summarize the mechanistic principles behind various antisense targets currently available for SMA therapy.
Acknowledgements
The authors wish to acknowledge J Seo, EW Ottesen and MD Howell for the valuable comments on the manuscript.
Financial & competing interests disclosure
This work was supported by grants from NIH (NS055925, NS072259 and NS080294 to RNS and NS060926 to CJ DiDonato), Salsbury Endowment (Iowa State University, IA, USA; to RN Singh), CureSMA (DID1214, to CJ DiDonato) and the Muscular Dystrophy Association (255785, to CJ DiDonato). ISS-N1 target (US7838657) was discovered in the Singh laboratory at UMASS Medical School (MA, USA). Inventors, including RN Singh, NN Singh and UMASS Medical School, are currently benefiting from licensing of ISS-N1 target to ISIS Pharmaceuticals. Iowa State University holds intellectual property rights on GCRS and ISS-N2 targets. Therefore, inventors including RN Singh, NN Singh and Iowa State University could potentially benefit from any future commercial exploitation of GCRS and ISS-N2 targets. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.