Work

Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide

Year: 2017

Type: article

Abstract: Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2017.03.036

Authors: Matthew D. Howell, Eric W. Ottesen, Natalia N. Singh, Rachel L. Anderson, Ravindra N. Singh

Institution: Iowa State University

Language: English

Topic: Neurogenetic and Muscular Disorders Research

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500