Engineered tRNAs suppress nonsense mutations in cells and in vivo

Suki Albers, Elizabeth C. Allen, Nikhil Bharti, Marcos Davyt, Disha Joshi, Carlos G. Perez-Garcia, Leonardo Santos, Rajesh Mukthavaram, Miguel Angel Delgado-Toscano, Brandon Molina, Kristen Kuakini, Maher Alayyoubi, Kyoung-Joo Jenny Park, Grishma Acharya, Jose A. Gonzalez, Amit Sagi, Susan E. Birket, Guillermo J. Tearney, Steven M. Rowe, Candela Manfredi, Jeong S. Hong, Kiyoshi Tachikawa, Priya Karmali, Daiki Matsuda, Eric J. Sorscher (), Pad Chivukula () and Zoya Ignatova ()
Additional contact information
Suki Albers: University of Hamburg
Elizabeth C. Allen: Arcturus Therapeutics
Nikhil Bharti: University of Hamburg
Marcos Davyt: University of Hamburg
Disha Joshi: Emory University
Carlos G. Perez-Garcia: Arcturus Therapeutics
Leonardo Santos: University of Hamburg
Rajesh Mukthavaram: Arcturus Therapeutics
Miguel Angel Delgado-Toscano: University of Hamburg
Brandon Molina: Arcturus Therapeutics
Kristen Kuakini: Arcturus Therapeutics
Maher Alayyoubi: Arcturus Therapeutics
Kyoung-Joo Jenny Park: Arcturus Therapeutics
Grishma Acharya: Arcturus Therapeutics
Jose A. Gonzalez: Arcturus Therapeutics
Amit Sagi: Arcturus Therapeutics
Susan E. Birket: University of Alabama at Birmingham
Guillermo J. Tearney: Wellman Center for Photomedicine, Massachusetts General Hospital
Steven M. Rowe: University of Alabama at Birmingham
Candela Manfredi: Emory University
Jeong S. Hong: Emory University
Kiyoshi Tachikawa: Arcturus Therapeutics
Priya Karmali: Arcturus Therapeutics
Daiki Matsuda: Arcturus Therapeutics
Eric J. Sorscher: Emory University
Pad Chivukula: Arcturus Therapeutics
Zoya Ignatova: University of Hamburg

Nature, 2023, vol. 618, issue 7966, 842-848

Abstract: Abstract Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2–7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP–sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.

Date: 2023
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DOI: 10.1038/s41586-023-06133-1

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