Journal
GENE THERAPY
Volume 24, Issue 9, Pages 520-526Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2017.34
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Funding
- US National Institutes of Health NIH [R01 NS055925]
- Iowa Center of Advanced Neurotoxicology (ICAN)
- Salsbury Endowment at Iowa State University
- NIH [R01 NS040275, R01 NS0682284]
- Cure SMA
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS040275, R01NS055925] Funding Source: NIH RePORTER
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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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