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Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa

Author

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  • Miranda L. Scalabrino

    (University of California
    Duke University School of Medicine)

  • Mishek Thapa

    (University of California
    Duke University School of Medicine)

  • Tian Wang

    (University of Southern California)

  • Alapakkam P. Sampath

    (University of California)

  • Jeannie Chen

    (University of Southern California)

  • Greg D. Field

    (University of California
    Duke University School of Medicine)

Abstract

Retinitis pigmentosa is an inherited photoreceptor degeneration that begins with rod loss followed by cone loss. This cell loss greatly diminishes vision, with most patients becoming legally blind. Gene therapies are being developed, but it is unknown how retinal function depends on the time of intervention. To uncover this dependence, we utilize a mouse model of retinitis pigmentosa capable of artificial genetic rescue. This model enables a benchmark of best-case gene therapy by removing variables that complicate answering this question. Complete genetic rescue was performed at 25%, 50%, and 70% rod loss (early, mid and late, respectively). Early and mid treatment restore retinal output to near wild-type levels. Late treatment retinas exhibit continued, albeit slowed, loss of sensitivity and signal fidelity among retinal ganglion cells, as well as persistent gliosis. We conclude that gene replacement therapies delivered after 50% rod loss are unlikely to restore visual function to normal. This is critical information for administering gene therapies to rescue vision.

Suggested Citation

  • Miranda L. Scalabrino & Mishek Thapa & Tian Wang & Alapakkam P. Sampath & Jeannie Chen & Greg D. Field, 2023. "Late gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44063-8
    DOI: 10.1038/s41467-023-44063-8
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    References listed on IDEAS

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    1. Greg D. Field & Jeffrey L. Gauthier & Alexander Sher & Martin Greschner & Timothy A. Machado & Lauren H. Jepson & Jonathon Shlens & Deborah E. Gunning & Keith Mathieson & Wladyslaw Dabrowski & Liam Pa, 2010. "Functional connectivity in the retina at the resolution of photoreceptors," Nature, Nature, vol. 467(7316), pages 673-677, October.
    2. Bates, Douglas & Mächler, Martin & Bolker, Ben & Walker, Steve, 2015. "Fitting Linear Mixed-Effects Models Using lme4," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 67(i01).
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