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