Campus Units

Biomedical Sciences

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

9-2017

Journal or Book Title

Gene Therapy

Volume

24

Issue

9

First Page

520

Last Page

526

DOI

10.1038/gt.2017.34

Abstract

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 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.

Comments

This is a manuscript of an article published as Singh, Natalia N., Matthew D. Howell, Elliot J. Androphy, and Ravindra N. Singh. "How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy." Gene therapy 24, no. 9 (2017): 520. doi: 10.1038/gt.2017.34. Posted with permission.

Copyright Owner

Macmillan Publishers Limited

Language

en

File Format

application/pdf

Published Version

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