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.