High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue

Muller, A.; Sullivan, J.; Schwarzer, W.; Wang, M.; Park-Windhol, C.; Klingler, B.; Matsell, J.; Hostettler, S.; Galliker, P.; Duman, M.; Hou, Y.; Balmer, P.; Virag, T.; Barrera, L. A.; Xu, Q.; Magda, D. P.; Kilin, F.; Khadka, A.; Quinodoz, M.; Hasler, P. W.; Moreau, P.-H.; Fellmann, L.; Azoulay, T.; Cattaneo, M.; Picelli, S.; Grison, A.; Cowan, C. S.; Janeschitz-Kriegl, L.; Kusnyerik, A.; Renner, M.; Nagy, Z. Z.; Szabo, A.; Rivolta, C.; Scholl, H. P. N.; Bryson, D.; Ciaramella, G.; Roska, B.; György, B.

doi:10.1101/2023.04.17.535579

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bioRxiv · 10.1101/2023.04.17.535579

High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue

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Abstract

Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector split-intein adenine base-editing strategy to correct the most common mutation in ABCA4 (c.5882G>A, p.G1961E). We optimized ABCA4 base editing in human models, including retinal organoids, iPSC-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal- and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in non-human primates, with an average editing of 37% of photoreceptors and 73% of RPE cells in vivo. The high editing rates in primates make way for precise and efficient gene editing in other neurodegenerative ocular diseases.

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Muller, A., Sullivan, J., Schwarzer, W., Wang, M., Park-Windhol, C., Klingler, B., Matsell, J., Hostettler, S., Galliker, P., Duman, M., Hou, Y., Balmer, P., Virag, T., Barrera, L. A., Xu, Q., Magda, D. P., Kilin, F., Khadka, A., Quinodoz, M., Hasler, P. W., Moreau, P.-H., Fellmann, L., Azoulay, T., Cattaneo, M., Picelli, S., Grison, A., Cowan, C. S., Janeschitz-Kriegl, L., Kusnyerik, A., Renner, M., Nagy, Z. Z., Szabo, A., Rivolta, C., Scholl, H. P. N., Bryson, D., Ciaramella, G., Roska, B., György, B.. 2023-04-17. High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue. https://doi.org/10.1101/2023.04.17.535579

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