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DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration
Tejal Aslesh, … , Rika Maruyama, Toshifumi Yokota
Tejal Aslesh, … , Rika Maruyama, Toshifumi Yokota
Published January 31, 2023
Citation Information: JCI Insight. 2023;8(5):e160516. https://doi.org/10.1172/jci.insight.160516.
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Research Article Genetics Muscle biology

DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration

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Abstract

Antisense oligonucleotide–mediated (AO-mediated) therapy is a promising strategy to treat several neurological diseases, including spinal muscular atrophy (SMA). However, limited delivery to the CNS with AOs administered intravenously or subcutaneously is a major challenge. Here, we demonstrate a single subcutaneous administration of cell-penetrating peptide DG9 conjugated to an AO called phosphorodiamidate morpholino oligomer (PMO) reached the CNS and significantly prolonged the median survival compared with unconjugated PMO and R6G-PMO in a severe SMA mouse model. Treated mice exhibited substantially higher expression of full-length survival of motor neuron 2 in both the CNS and systemic tissues compared with nontreated and unmodified AO–treated mice. The treatment ameliorated the atrophic musculature and improved breathing function accompanied by improved muscle strength and innervation at the neuromuscular junction with no signs of apparent toxicity. We also demonstrated DG9-conjugated PMO localized in nuclei in the spinal cord and brain after subcutaneous injections. Our data identify DG9 peptide conjugation as a powerful way to improve the efficacy of AO-mediated splice modulation. Finally, DG9-PMO is a promising therapeutic option to treat SMA and other neurological diseases, overcoming the necessity for intrathecal injections and treating body-wide tissues without apparent toxicity.

Authors

Tejal Aslesh, Esra Erkut, Jun Ren, Kenji Rowel Q. Lim, Stanley Woo, Susan Hatlevig, Hong M. Moulton, Simon Gosgnach, John Greer, Rika Maruyama, Toshifumi Yokota

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Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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