Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a fatal disorder caused by loss of dystrophin, a protein essential for muscle cell integrity. To date, no therapeutic has restored full-length dystrophin. Suppressor transfer RNAs (sup-tRNAs) have the potential to treat the ∼15% of patients with DMD and nonsense mutations. We have evolved highly potent UAA sup-tRNAs through an extensive mutagenesis screening campaign, optimized our adeno-associated virus (AAV) expression vectors, and developed efficient RNA polymerase III promoters. We show that systemic delivery of these sup-tRNAs restores full-length dystrophin and recovers muscle strength and motor function in mice at lower doses than AAV microdystrophin therapies. We see no adverse toxicology and observe proteome-wide reversion of molecular pathophysiology. These data establish sup-tRNAs as a promising therapeutic platform for DMD and other disorders.

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Publication Details

Journal
Science Advances
Published
2026-09-09
DOI
https://doi.org/10.1126/sciadv.aeg3466
Primary Topic
Muscle Physiology and Disorders
Type
article
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article

Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy

Paul L. Kaplan, Peter M. Eimon, Steffany Villaseñor, Teerithveen Pasricha et al.
Science Advances
Muscle Physiology and Disorders
article

Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy

Paul L. Kaplan, Peter M. Eimon, Steffany Villaseñor, Teerithveen Pasricha, Michael E. Calhoun, W. Mannheim, Delilah Jewel, Jeff Coller, Harvey F. Lodish, Julien Oury, Gokul Sriman Thanigai Arasu, Sean McFarland, Alexis Dilts, Nitusingh Thakur, Ying-Hsin Chen, Nathan Strozewski, Joel Wen, McKenna Montminy, Sophia Zheng, Victoria Rose
article en

Abstract

Duchenne muscular dystrophy (DMD) is a fatal disorder caused by loss of dystrophin, a protein essential for muscle cell integrity. To date, no therapeutic has restored full-length dystrophin. Suppressor transfer RNAs (sup-tRNAs) have the potential to treat the ∼15% of patients with DMD and nonsense mutations. We have evolved highly potent UAA sup-tRNAs through an extensive mutagenesis screening campaign, optimized our adeno-associated virus (AAV) expression vectors, and developed efficient RNA polymerase III promoters. We show that systemic delivery of these sup-tRNAs restores full-length dystrophin and recovers muscle strength and motor function in mice at lower doses than AAV microdystrophin therapies. We see no adverse toxicology and observe proteome-wide reversion of molecular pathophysiology. These data establish sup-tRNAs as a promising therapeutic platform for DMD and other disorders.

Science AdvancesVol. 12(37)
Johns Hopkins University (US), LI-COR Biosciences (United States) (US), University of California, San Francisco (US), University of Michigan (US), Whitehead Institute for Biomedical Research (US), Massachusetts Institute of Technology (US), University of Pennsylvania (US), University of California, Berkeley (US), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 17%
Muscle Physiology and Disorders
DOIOpen Access PDFOpenAlex
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