Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. With the recent US Food and Drug Administration approval of nusinersen (Spinraza), the potential for correction of SMN2 exon 7 splicing as an SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here, we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.
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The nonprofit organization Cure SMA (formerly Families of SMA) supported the initial studies in the laboratories of Drs Ravindra Singh and Elliot Androphy, which led to the discovery of the ISS-N1 target at the University Massachusetts Medical School. RNS is supported by US National Institutes of Health NIH R01 NS055925, Iowa Center of Advanced Neurotoxicology (ICAN) and Salsbury Endowment at Iowa State University. EJA is grateful for support from NIH Grants R01 NS040275 and R01 NS0682284 and Cure SMA.
The ISS-N1 target (US7838657) was discovered in the Singh laboratory at UMass Medical School (MA, USA). Inventors, including RNS, NNS, EJA and UMASS Medical School, are currently benefiting from licensing of the ISS-N1 target to Ionis Pharmaceuticals. Iowa State University holds intellectual property rights on GC-rich sequence (GCRS) and ISS-N2 targets. Therefore, inventors including RNS, NNS and Iowa State University could potentially benefit from any future commercial exploitation of GCRS and ISS-N2 targets. MDH has no conflict of interest to declare.
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Singh, N., Howell, M., Androphy, E. et al. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther 24, 520–526 (2017). https://doi.org/10.1038/gt.2017.34
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