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‘Hit and run’ therapy averts macular degeneration

Nature Biomedical Engineering volume 5, pages 132–133 (2021)Cite this article

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Subretinal delivery of lentiviruses bearing Cas9 mRNA and a guide RNA targeting the Vegfa gene reduces the development of choroidal neovascularization in a mouse model of wet age-related macular degeneration.

Cai and co-authors generated mRNA-encoding plasmids coding for a coat protein of the MS2 phage fused to the N terminus of the lentivirus Gag–Pol polyprotein backbone with an HIV-1 protease-cleavage site inserted between the two fused proteins (Fig. 1a). Cas9 mRNA was packaged into the lentivirus particles (produced in HEK293T cells) via aptamer sequences binding to the expressed MS2 protein. The Vegfa-targeting gRNA was supplied by a U3-promoter-driven cassette in an integration-deficient genome. Lentiviral particles delivered by subretinal injection in C57BL/6J mice led to editing rates of up to 44% in the Vegfa locus of cells in retinal pigment epithelium (the only source of VEGFA protein in the posterior part of the eyes), and to a pronounced reduction of VEGFA levels two weeks after injection. No innate or adaptive immune responses to Cas9 were detected. In the mouse model of wet age-related macular degeneration, induction of CNV (via exposure to high-intensity laser pulses around the optic disc) 7 days after subretinal injection of the lentiviral particles led to a marked reduction of CNV, thus indicating that the reduction in VEGFA levels by this therapy is sufficient to prevent macular degeneration (Fig. 1b).

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Fig. 1: Lentiviral delivery of Cas9 mRNA and a Vegfa-targeting gRNA to retinal epithelium largely prevents the development of wet age-related macular degeneration in mice.

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Authors and Affiliations

  1. Department of Infectious Diseases/Virology, Medical Faculty, University of Heidelberg, Heidelberg, Germany

    Felix Bubeck & Dirk Grimm

  2. BioQuant, University of Heidelberg, Heidelberg, Germany

    Felix Bubeck & Dirk Grimm

  3. German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), Heidelberg, Germany

    Dirk Grimm

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  1. Felix Bubeck
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  2. Dirk Grimm
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Correspondence to Dirk Grimm.

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Competing interests

D.G. is a co-founder and shareholder of AaviGen GmbH. F.B. and D.G. have filed patent applications related to CRISPR technologies and gene delivery via adeno-associated viruses.

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Bubeck, F., Grimm, D. ‘Hit and run’ therapy averts macular degeneration. Nat Biomed Eng 5, 132–133 (2021). https://doi.org/10.1038/s41551-021-00690-4

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