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Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo.

Publication ,  Journal Article
Meganck, RM; Borchardt, EK; Castellanos Rivera, RM; Scalabrino, ML; Wilusz, JE; Marzluff, WF; Asokan, A
Published in: Mol Ther Nucleic Acids
December 7, 2018

Circular RNAs (circRNAs) are long-lived, covalently closed RNAs that are abundantly expressed and evolutionarily conserved across eukaryotes. Possible functions ranging from microRNA (miRNA) and RNA binding protein sponges to regulators of transcription and translation have been proposed. Here we describe the design and characterization of recombinant adeno-associated viral (AAV) vectors packaging transgene cassettes containing intronic sequences that promote backsplicing to generate circularized RNA transcripts. Using a split GFP transgene, we demonstrate the capacity of vectors containing different flanking intronic sequences to efficiently drive persistent circRNA formation in vitro. Further, translation from circRNA is efficiently driven by an internal ribosomal entry site (IRES). Upon injecting AAV vectors encoding circRNA in mice, we observed robust transgene expression in the heart, but low transduction in the liver for the intronic elements tested. Expression in the murine brain was restricted to astrocytes following systemic or intracranial administration, while intravitreal injection in the eye yielded robust transgene expression across multiple retinal cell layers. These results highlight the potential for exploiting AAV-based circRNA expression to study circRNA function and tissue-specific regulation in animal models, as well as development of therapeutic platforms using this approach.

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Published In

Mol Ther Nucleic Acids

DOI

ISSN

2162-2531

Publication Date

December 7, 2018

Volume

13

Start / End Page

89 / 98

Location

United States

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology
 

Citation

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ICMJE
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Meganck, R. M., Borchardt, E. K., Castellanos Rivera, R. M., Scalabrino, M. L., Wilusz, J. E., Marzluff, W. F., & Asokan, A. (2018). Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo. Mol Ther Nucleic Acids, 13, 89–98. https://doi.org/10.1016/j.omtn.2018.08.008
Meganck, Rita M., Erin K. Borchardt, Ruth M. Castellanos Rivera, Miranda L. Scalabrino, Jeremy E. Wilusz, William F. Marzluff, and Aravind Asokan. “Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo.Mol Ther Nucleic Acids 13 (December 7, 2018): 89–98. https://doi.org/10.1016/j.omtn.2018.08.008.
Meganck RM, Borchardt EK, Castellanos Rivera RM, Scalabrino ML, Wilusz JE, Marzluff WF, et al. Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo. Mol Ther Nucleic Acids. 2018 Dec 7;13:89–98.
Meganck, Rita M., et al. “Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo.Mol Ther Nucleic Acids, vol. 13, Dec. 2018, pp. 89–98. Pubmed, doi:10.1016/j.omtn.2018.08.008.
Meganck RM, Borchardt EK, Castellanos Rivera RM, Scalabrino ML, Wilusz JE, Marzluff WF, Asokan A. Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo. Mol Ther Nucleic Acids. 2018 Dec 7;13:89–98.
Journal cover image

Published In

Mol Ther Nucleic Acids

DOI

ISSN

2162-2531

Publication Date

December 7, 2018

Volume

13

Start / End Page

89 / 98

Location

United States

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology