Utilizing AAV-mediated LEAPER 2.0 for programmable RNA editing in non-human primates and nonsense mutation correction in humanized Hurler syndrome mice.

Genome Biol

Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, People's Republic of China.

Published: October 2023

AI Article Synopsis

  • The study focuses on using adenosine deaminases acting on RNA (ADAR) for precise editing of RNA, addressing concerns about its effectiveness for therapy due to variable ADAR expression in tissues and species.
  • Researchers found that delivering circular ADAR-recruiting RNAs (arRNAs) using AAV (adeno-associated virus) led to around 80% editing efficiency in non-human primates without any noticeable toxicity over a 4 to 13-week period.
  • The successful correction of a genetic defect in a mouse model of Hurler syndrome suggests that AAV-delivered circular arRNAs could be a promising approach for therapeutic applications in humans.

Article Abstract

Background: The endogenous adenosine deaminases acting on RNA (ADAR) have been harnessed to facilitate precise adenosine-to-inosine editing on RNAs. However, the practicability of this approach for therapeutic purposes is still ambiguous due to the variable expression of intrinsic ADAR across various tissues and species, as well as the absence of all-encompassing confirmation for delivery methods.

Results: In this study, we demonstrate that AAV-mediated delivery of circular ADAR-recruiting RNAs (arRNAs) achieves effective RNA editing in non-human primates at dosages suitable for therapy. Within a time frame of 4 to 13 weeks following infection, the editing efficiency in AAV-infected cells can reach approximately 80%, with no discernible toxicity, even at elevated dosages. In addition, when AAV-delivered circular arRNAs are systematically administered to a humanized mouse model of Hurler syndrome, it rectifies the premature stop codon precisely and restores the functionality of IDUA enzyme encoded by the Hurler causative gene in multiple organs.

Conclusions: These discoveries considerably bolster the prospects of employing AAV-borne circular arRNAs for therapeutic applications and exploratory translational research.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10591355PMC
http://dx.doi.org/10.1186/s13059-023-03086-6DOI Listing

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