Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model

Author:

Sheng Lei123,Rigo Frank4,Bennett C Frank4,Krainer Adrian R3ORCID,Hua Yimin135ORCID

Affiliation:

1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China

2. Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China

3. Cold Spring Harbor Laboratory, PO Box 100, Cold Spring Harbor, New York, NY 11724, USA

4. Ionis Pharmaceuticals, Carlsbad, CA 92010, USA

5. Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, China

Abstract

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.

Funder

National Natural Science Foundation of China

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics

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