mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy

Lisa Maria Riedmayr, Klara Sonnie Hinrichsmeyer, Stefan Bernhard Thalhammer, David Manuel Mittas, Nina Karguth, Dina Yehia Otify, Sybille Böhm, Valentin Johannes Weber, Michael David Bartoschek, Victoria Splith, Manuela Brümmer, Raphael Ferreira, Nanda Boon, Gabriele Maria Wögenstein, Christian Grimm, Jan Wijnholds, Verena Mehlfeld, Stylianos Michalakis, Stefanie Fenske, Martin Biel and Elvir Becirovic ()
Additional contact information
Lisa Maria Riedmayr: LMU Munich
Klara Sonnie Hinrichsmeyer: LMU Munich
Stefan Bernhard Thalhammer: LMU Munich
David Manuel Mittas: LMU Munich
Nina Karguth: LMU Munich
Dina Yehia Otify: LMU Munich
Sybille Böhm: ViGeneron GmbH
Valentin Johannes Weber: University of Zurich
Michael David Bartoschek: ViGeneron GmbH
Victoria Splith: ViGeneron GmbH
Manuela Brümmer: LMU Munich
Raphael Ferreira: Harvard Medical School
Nanda Boon: Leiden University Medical Center (LUMC)
Gabriele Maria Wögenstein: University of Zurich
Christian Grimm: University of Zurich
Jan Wijnholds: Leiden University Medical Center (LUMC)
Verena Mehlfeld: LMU Munich
Stylianos Michalakis: LMU Munich
Stefanie Fenske: LMU Munich
Martin Biel: LMU Munich
Elvir Becirovic: University of Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Large genes including several CRISPR-Cas modules like gene activators (CRISPRa) require dual adeno-associated viral (AAV) vectors for an efficient in vivo delivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based on reconstitution via mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerous in vitro models, in human organoids, and in vivo. Furthermore, REVeRT can functionally reconstitute a CRISPRa module targeting genes in various mouse tissues and organs in single or multiplexed approaches upon different routes of administration. Finally, REVeRT enabled the reconstitution of full-length ABCA4 after intravitreal injection in a mouse model of Stargardt disease. Due to its flexibility and efficiency REVeRT harbors great potential for basic research and clinical applications.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42386-0

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DOI: 10.1038/s41467-023-42386-0

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