AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice

Jiaming Wang, Yue Zhang, Craig A. Mendonca, Onur Yukselen, Khaja Muneeruddin, Lingzhi Ren, Jialing Liang, Chen Zhou, Jun Xie, Jia Li, Zhong Jiang, Alper Kucukural, Scott A. Shaffer, Guangping Gao () and Dan Wang ()
Additional contact information
Jiaming Wang: University of Massachusetts Chan Medical School
Yue Zhang: University of Massachusetts Chan Medical School
Craig A. Mendonca: University of Massachusetts Chan Medical School
Onur Yukselen: University of Massachusetts Chan Medical School
Khaja Muneeruddin: University of Massachusetts Chan Medical School
Lingzhi Ren: University of Massachusetts Chan Medical School
Jialing Liang: University of Massachusetts Chan Medical School
Chen Zhou: University of Massachusetts Chan Medical School
Jun Xie: University of Massachusetts Chan Medical School
Jia Li: University of Massachusetts Chan Medical School
Zhong Jiang: University of Massachusetts Chan Medical School
Alper Kucukural: University of Massachusetts Chan Medical School
Scott A. Shaffer: University of Massachusetts Chan Medical School
Guangping Gao: University of Massachusetts Chan Medical School
Dan Wang: University of Massachusetts Chan Medical School

Nature, 2022, vol. 604, issue 7905, 343-348

Abstract: Abstract Gene therapy is a potentially curative medicine for many currently untreatable diseases, and recombinant adeno-associated virus (rAAV) is the most successful gene delivery vehicle for in vivo applications1–3. However, rAAV-based gene therapy suffers from several limitations, such as constrained DNA cargo size and toxicities caused by non-physiological expression of a transgene4–6. Here we show that rAAV delivery of a suppressor tRNA (rAAV.sup-tRNA) safely and efficiently rescued a genetic disease in a mouse model carrying a nonsense mutation, and effects lasted for more than 6 months after a single treatment. Mechanistically, this was achieved through a synergistic effect of premature stop codon readthrough and inhibition of nonsense-mediated mRNA decay. rAAV.sup-tRNA had a limited effect on global readthrough at normal stop codons and did not perturb endogenous tRNA homeostasis, as determined by ribosome profiling and tRNA sequencing, respectively. By optimizing the AAV capsid and the route of administration, therapeutic efficacy in various target tissues was achieved, including liver, heart, skeletal muscle and brain. This study demonstrates the feasibility of developing a toolbox of AAV-delivered nonsense suppressor tRNAs operating on premature termination codons (AAV-NoSTOP) to rescue pathogenic nonsense mutations and restore gene function under endogenous regulation. As nonsense mutations account for 11% of pathogenic mutations, AAV-NoSTOP can benefit a large number of patients. AAV-NoSTOP obviates the need to deliver a full-length protein-coding gene that may exceed the rAAV packaging limit, elicit adverse immune responses or cause transgene-related toxicities. It therefore represents a valuable addition to gene therapeutics.

Date: 2022
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DOI: 10.1038/s41586-022-04533-3

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