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In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration

Author

Listed:
  • Elliot H. Choi

    (University of California
    Case Western Reserve University)

  • Susie Suh

    (University of California
    Case Western Reserve University)

  • Andrzej T. Foik

    (Polish Academy of Sciences)

  • Henri Leinonen

    (University of California)

  • Gregory A. Newby

    (Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
    Harvard University
    Harvard University)

  • Xin D. Gao

    (Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
    Harvard University
    Harvard University)

  • Samagya Banskota

    (Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
    Harvard University
    Harvard University)

  • Thanh Hoang

    (Johns Hopkins University School of Medicine)

  • Samuel W. Du

    (University of California
    University of California)

  • Zhiqian Dong

    (University of California)

  • Aditya Raguram

    (Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
    Harvard University
    Harvard University)

  • Sajeev Kohli

    (Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
    Harvard University
    Harvard University)

  • Seth Blackshaw

    (Johns Hopkins University School of Medicine)

  • David C. Lyon

    (University of California)

  • David R. Liu

    (Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
    Harvard University
    Harvard University)

  • Krzysztof Palczewski

    (University of California
    University of California
    University of California
    University of California)

Abstract

Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting in early visual impairment. It is therefore crucial to develop a robust therapy that not only compensates for lost RPE65 function but also protects photoreceptors from further degeneration. Here, we show that in vivo correction of an Rpe65 mutation by adenine base editor (ABE) prolongs the survival of cones in an LCA mouse model. In vitro screening of ABEs and sgRNAs enables the identification of a variant that enhances in vivo correction efficiency. Subretinal delivery of ABE and sgRNA corrects up to 40% of Rpe65 transcripts, restores cone-mediated visual function, and preserves cones in LCA mice. Single-cell RNA-seq reveals upregulation of genes associated with cone phototransduction and survival. Our findings demonstrate base editing as a potential gene therapy that confers long-lasting retinal protection.

Suggested Citation

  • Elliot H. Choi & Susie Suh & Andrzej T. Foik & Henri Leinonen & Gregory A. Newby & Xin D. Gao & Samagya Banskota & Thanh Hoang & Samuel W. Du & Zhiqian Dong & Aditya Raguram & Sajeev Kohli & Seth Blac, 2022. "In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29490-3
    DOI: 10.1038/s41467-022-29490-3
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    References listed on IDEAS

    as
    1. Gregory A. Newby & Jonathan S. Yen & Kaitly J. Woodard & Thiyagaraj Mayuranathan & Cicera R. Lazzarotto & Yichao Li & Heather Sheppard-Tillman & Shaina N. Porter & Yu Yao & Kalin Mayberry & Kelcee A. , 2021. "Base editing of haematopoietic stem cells rescues sickle cell disease in mice," Nature, Nature, vol. 595(7866), pages 295-302, July.
    2. Luke W. Koblan & Michael R. Erdos & Christopher Wilson & Wayne A. Cabral & Jonathan M. Levy & Zheng-Mei Xiong & Urraca L. Tavarez & Lindsay M. Davison & Yantenew G. Gete & Xiaojing Mao & Gregory A. Ne, 2021. "In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice," Nature, Nature, vol. 589(7843), pages 608-614, January.
    3. Kiran Musunuru & Alexandra C. Chadwick & Taiji Mizoguchi & Sara P. Garcia & Jamie E. DeNizio & Caroline W. Reiss & Kui Wang & Sowmya Iyer & Chaitali Dutta & Victoria Clendaniel & Michael Amaonye & Aar, 2021. "In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates," Nature, Nature, vol. 593(7859), pages 429-434, May.
    4. Alexis C. Komor & Yongjoo B. Kim & Michael S. Packer & John A. Zuris & David R. Liu, 2016. "Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage," Nature, Nature, vol. 533(7603), pages 420-424, May.
    Full references (including those not matched with items on IDEAS)

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