Comparison of the Efficacy of MOE and PMO Modifications of Systemic Antisense Oligonucleotides in a Severe SMA Mouse Model

Sheng, L., Rigo, F., Bennett, C. F., Krainer, A. R., Hua, Y. (April 2020) Comparison of the Efficacy of MOE and PMO Modifications of Systemic Antisense Oligonucleotides in a Severe SMA Mouse Model. Nucleic Acids Research, 6 (48). pp. 2853-2865. ISSN 0305-1048 (Public Dataset)

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URL: https://pubmed.ncbi.nlm.nih.gov/32103257/

DOI: 10.1093/nar/gkaa126

Abstract

Spinal muscular atrophy (SMA) is a motor neuron disease. Nusinersen, a splice-switching antisense oligonucleotide (ASO), was the first approved drug to treat SMA. Based on prior preclinical studies, both 2'-O-methoxyethyl (MOE) with a phosphorothioate backbone and morpholino with a phosphorodiamidate backbone-with the same or extended target sequence as nusinersen-displayed efficient rescue of SMA mouse models. Here, we compared the therapeutic efficacy of these two modification chemistries in rescue of a severe mouse model using ASO10-29-a 2-nt longer version of nusinersen-via subcutaneous injection. Although both chemistries efficiently corrected SMN2 splicing in various tissues, restored motor function and improved the integrity of neuromuscular junctions, MOE-modified ASO10-29 (MOE10-29) was more efficacious than morpholino-modified ASO10-29 (PMO10-29) at the same molar dose, as seen by longer survival, greater body-weight gain and better preservation of motor neurons. Time-course analysis revealed that MOE10-29 had more persistent effects than PMO10-29. On the other hand, PMO10-29 appears to more readily cross an immature blood-brain barrier following systemic administration, showing more robust initial effects on SMN2 exon 7 inclusion, but less persistence in the central nervous system. We conclude that both modifications can be effective as splice-switching ASOs in the context of SMA and potentially other diseases, and discuss the advantages and disadvantages of each.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons organism description > animal > mammal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > motor neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > motor neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > motor neurons organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > neuromuscular junction organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing organism description > animal > mammal > rodent diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions
CSHL Authors:	Krainer, Adrian R. Hua, Yimin Sheng, Lei
Communities:	CSHL labs > Krainer lab CSHL Cancer Center Program > Gene Regulation and Inheritance Program
Depositing User:	Adrian Gomez
Date:	6 April 2020
Date Deposited:	06 Apr 2020 14:26
Last Modified:	01 Feb 2024 18:30
PMCID:	PMC7102994
Related URLs:	Publisher
Dataset ID:	https://academic.oup.com/nar/article/48/6/2853/5760755#supplementary-data
URI:	https://repository.cshl.edu/id/eprint/39225

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