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

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Ottesen, Eric
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Singh, Ravindra
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Biomedical Sciences

The Department of Biomedical Sciences aims to provide knowledge of anatomy and physiology in order to understand the mechanisms and treatment of animal diseases. Additionally, it seeks to teach the understanding of drug-action for rational drug-therapy, as well as toxicology, pharmacodynamics, and clinical drug administration.

The Department of Biomedical Sciences was formed in 1999 as a merger of the Department of Veterinary Anatomy and the Department of Veterinary Physiology and Pharmacology.

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  • College of Veterinary Medicine (parent college)
  • Department of Veterinary Anatomy (predecessor, 1997)
  • Department of Veterinary Physiology and Pharmacology (predecessor, 1997)

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College of Veterinary Medicine
The Iowa State University College of Veterinary Medicine aspires to be a preeminent institution recognized for excellence in professional and graduate education and the application of knowledge to promote animal and human health, while providing a caring and supportive educational and work environment where all can succeed.
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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.
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: © The Author(s) 2024.This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (, 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.