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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DOI: 10.1093/nar/gkaa126


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
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Adrian Gomez
Date: 6 April 2020
Date Deposited: 06 Apr 2020 14:26
Last Modified: 06 Apr 2020 14:26
PMCID: PMC7102994
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