Cardio‐respiratory and phenotypic rescue of dystrophin/utrophin‐deficient mice by combination therapy

Cardio‐respiratory and phenotypic rescue of dystrophin/utrophin‐deficient mice by combination therapy

EMBO reports

10.15252/embr.202153955

http://dx.doi.org/10.15252/embr.202153955

Caorui Lin, Gang Han, Lulu Jia, Yiwen Zhao, Jun Song, Ning Ran, Toshifumi Yokota, Yiqi Seow, HaiFang Yin

Biochemistry, Molecular Biology, genetics

08 April 2022

Lin, C., Han, G., Jia, L., Zhao, Y., Song, J., Ran, N., Yokota, T., Seow, Y., & Yin, H. (2022). Cardio‐respiratory and phenotypic rescue of dystrophin/utrophin‐deficient mice by combination therapy. EMBO Reports, 23(6). Portico. https://doi.org/10.15252/embr.202153955

Duchenne muscular dystrophy (DMD) is a systemic progressive muscular disease caused by frame-disrupting mutations in the DMD gene. Although exon-skipping antisense oligonucleotides (AOs) are clinically approved and can correct DMD, insufficient muscle delivery limits efficacy. If AO activity can be enhanced by safe dietary supplements, clinical trials for efficacy can be undertaken rapidly to benefit patients. We showed previously that intravenous glycine enhanced phosphorodiamidate morpholino oligomer (PMO) delivery to peripheral muscles in mdx mice. Here, we demonstrate that the combination of oral glycine and metformin with intravenous PMO enhances PMO activity, dystrophin restoration, extends lifespan, and improves body-wide function and phenotypic rescue of dystrophin /utrophin double knock-out (DKO) mice without any overt adverse effects. The DKO mice treated with the combination without altering the approved administration protocol of PMO show improved cardio-respiratory and behavioral functions. Metformin and glycine individually are ineffective in DMD patients, but the combination of PMO with clinically-approved oral glycine and metformin might improve the efficacy of the treatment also in DMD patients. Our data suggest that this combination therapy might be an attractive therapy for DMD and potentially other muscle diseases requiring systemic treatment with AOs.

Publisher Copyright

This study was funded by National Key R&D Program of China (Grant No.2017YFC1001902), National Natural Science Foundation of China (Grant No. 81802124and81672124); Postdoctoral Science Foundation of China (Grant No. 2017M611176); Tianjin Municipal Science and Technology Key Project (Grant No. 18JCQNJC79400); Tianjin Research Innovation Project for Postgraduate Students (2019YJSB114) and Tianjin Municipal 13th 5-year plan (Tianjin Medical University Talent Project).

This is the peer reviewed version of the following article: Lin, C., Han, G., Jia, L., Zhao, Y., Song, J., Ran, N., Yokota, T., Seow, Y., & Yin, H. (2022). Cardio‐respiratory and phenotypic rescue of dystrophin/utrophin‐deficient mice by combination therapy. EMBO Reports, 23(6). Portico. https://doi.org/10.15252/embr.202153955, which has been published in final form at doi.org/10.15252/embr.202153955, This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

https://oar.a-star.edu.sg/communities-collections/articles/18724

1469-3178
1469-221X

Institute of Bioengineering and Bioimaging