Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene

dc.contributor.author Ottesen, Eric
dc.contributor.author Singh, Ravindra
dc.contributor.department Biomedical Sciences
dc.contributor.department College of Veterinary Medicine
dc.date.accessioned 2024-02-29T15:59:19Z
dc.date.available 2024-02-29T15:59:19Z
dc.date.issued 2024-02-19
dc.description.abstract Spinal muscular atrophy (SMA) is treated by increasing the level of Survival Motor Neuron (SMN) protein through correction of SMN2 exon 7 skipping or exogenous expression of SMN through gene therapy. Currently available therapies have multiple shortcomings, including poor body-wide distribution, invasive delivery, and potential negative consequences due to high doses needed for clinical efficacy. Here we test the effects of a combination treatment of a splice-correcting antisense oligonucleotide (ASO) Anti-N1 with the small compounds risdiplam and branaplam. We show that a low-dose treatment of Anti-N1 with either compound produces a synergistic effect on the inclusion of SMN2 exon 7 in SMA patient fibroblasts. Using RNA-Seq, we characterize the transcriptomes of cells treated with each compound as well as in combination. Although high doses of each individual treatment trigger widespread perturbations of the transcriptome, combination treatment of Anti-N1 with risdiplam and branaplam results in minimal disruption of gene expression. For individual genes targeted by the 3 compounds, we observe little to no additive effects of combination treatment. Overall, we conclude that the combination treatment of a splice-correcting ASO with small compounds represents a promising strategy for achieving a high level of SMN expression while minimizing the risk of off-target effects.
dc.description.comments This article is published as Ottesen, Eric W., and Ravindra N. Singh. "Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene." Neuroscience Insights 19 (2024): 26331055241233596. doi: https://doi.org/10.1177/26331055241233596. © The Author(s) 2024.This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE.
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/arY47EZv
dc.language.iso en
dc.publisher Sage Journals
dc.source.uri https://doi.org/10.1177/26331055241233596 *
dc.subject.disciplines DegreeDisciplines::Medicine and Health Sciences::Analytical, Diagnostic and Therapeutic Techniques and Equipment
dc.subject.keywords Spinal muscular atrophy (SMA)
dc.subject.keywords Survival motor neuron (SMN)
dc.subject.keywords Antisense oligonucleotide
dc.subject.keywords ASO
dc.subject.keywords ISS-N1
dc.subject.keywords Risdiplam
dc.subject.keywords Branaplam
dc.subject.keywords Nusinersen
dc.subject.keywords Anti-N1
dc.title Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene
dc.type Article
dspace.entity.type Publication
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