PT  - JOURNAL ARTICLE
AU  - Hart, Cora C.
AU  - Lee, Young il
AU  - Xie, Jun
AU  - Gao, Guangping
AU  - Hammers, David W.
AU  - Sweeney, H. Lee
TI  - Potential limitations of micro-dystrophin gene therapy for Duchenne muscular dystrophy
AID  - 10.1101/2022.10.02.510519
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.02.510519
4099  - http://biorxiv.org/content/early/2022/10/05/2022.10.02.510519.short
4100  - http://biorxiv.org/content/early/2022/10/05/2022.10.02.510519.full
AB  - Adeno-associated viruses (AAVs) expressing versions of truncated dystrophin (micro-dystrophins) are being delivered at high doses to patients with Duchenne muscular dystrophy (DMD) in clinical trials. We examined this strategy with two different micro-dystrophins, similar to those currently in clinical trials, in a severe mouse model of DMD, the D2.mdx mouse, using doses of AAV comparable to those used in the clinical trials. We achieved high levels of micro-dystrophin expression in striated muscle with cardiac expression ∼10 fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of the skeletal muscle disease is observed. Surprisingly, a lethal acceleration of cardiac disease progression occurs with one of the micro-dystrophins, while the second appears to benefit the heart. The detrimental impact on the heart in the first case appears to be caused by the high levels of micro-dystrophin in the heart resulting in competition between micro-dystrophin and utrophin at the cardiomyocyte membrane. While the significance of these observations for patients currently being treated with AAV-micro-dystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown, it suggests that micro-dystrophin treatments may need to be carefully titrated to avoid high levels of expression in the heart.Competing Interest StatementThe authors have declared no competing interest.