Singh, Natalia N.Howell, Matthew D.Androphy, Elliot J.Singh, Ravindra N.2018-03-142018-03-142017-09Singh, N. N., Howell, M. D., Androphy, E. J., & Singh, R. N. (2017). How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Therapy, 24(9), 520–526. https://doi.org/10.1038/gt.2017.340969-7128https://hdl.handle.net/1805/15545Spinal 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 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a 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.en-USPublisher PolicySpinal muscular atrophygeneticsinfant mortalityISS-N1Article