High-efficiency base editing in the retina in primates and human tissues

Alissa Muller; Jack Sullivan; Wibke Schwarzer; Mantian Wang; Cindy Park-Windhol; Pascal W Hasler; Lucas Janeschitz-Kriegl; Mert Duman; Beryll Klingler; Jane Matsell; Simon Manuel Hostettler; Patricia Galliker; Yanyan Hou; Pierre Balmer; Tamás Virág; Luis Alberto Barrera; Lauren Young; Quan Xu; Dániel Péter Magda; Ferenc Kilin; Arogya Khadka; Pierre-Henri Moreau; Lyne Fellmann; Thierry Azoulay; Mathieu Quinodoz; Duygu Karademir; Juna Leppert; Alex Fratzl; Georg Kosche; Ruchi Sharma; Jair Montford; Marco Cattaneo; Mikaël Croyal; Therese Cronin; Simone Picelli; Alice Grison; Cameron S Cowan; Ákos Kusnyerik; Philipp Anders; Magdalena Renner; Zoltán Zsolt Nagy; Arnold Szabó; Kapil Bharti; Carlo Rivolta; Hendrik P N Scholl; David Bryson; Giuseppe Ciaramella; Botond Roska; Bence György

doi:10.1038/s41591-024-03422-8

High-efficiency base editing in the retina in primates and human tissues

Nat Med. 2025 Jan 8. doi: 10.1038/s41591-024-03422-8. Online ahead of print.

Authors

Alissa Muller^{1

2}, Jack Sullivan³, Wibke Schwarzer^{1

2}, Mantian Wang^{1

2}, Cindy Park-Windhol³, Pascal W Hasler², Lucas Janeschitz-Kriegl^{1

2}, Mert Duman^{1

2}, Beryll Klingler^{1

2}, Jane Matsell^{1

2}, Simon Manuel Hostettler^{1

2}, Patricia Galliker^{1

2}, Yanyan Hou^{1

2}, Pierre Balmer^{1

2}, Tamás Virág³, Luis Alberto Barrera³, Lauren Young³, Quan Xu^{1

2}, Dániel Péter Magda⁴, Ferenc Kilin⁴, Arogya Khadka³, Pierre-Henri Moreau⁵, Lyne Fellmann⁵, Thierry Azoulay⁶, Mathieu Quinodoz^{1

2

7}, Duygu Karademir^{1

2}, Juna Leppert^{1

2}, Alex Fratzl^{1

2}, Georg Kosche^{1

2}, Ruchi Sharma⁸, Jair Montford⁸, Marco Cattaneo^{1

2

9}, Mikaël Croyal^{10

11}, Therese Cronin¹², Simone Picelli^{1

2}, Alice Grison^{1

2}, Cameron S Cowan^{1

2}, Ákos Kusnyerik^{1

2}, Philipp Anders^{1

2}, Magdalena Renner^{1

2}, Zoltán Zsolt Nagy¹³, Arnold Szabó⁴, Kapil Bharti⁸, Carlo Rivolta^{1

2

7}, Hendrik P N Scholl^{1

2

14

15}, David Bryson³, Giuseppe Ciaramella³, Botond Roska^{16

17

18}, Bence György^{19

20}

Affiliations

¹ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
² Department of Ophthalmology, University of Basel, Basel, Switzerland.
³ Beam Therapeutics, Cambridge, MA, USA.
⁴ Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
⁵ SILABE, Université de Strasbourg, Niederhausbergen, France.
⁶ Clinique Vétérinaire Agoravet, Strasbourg, France.
⁷ Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
⁸ Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Clinical Research, University of Basel, Basel, Switzerland.
¹⁰ Nantes Université, CNRS, INSERM, L'institut du thorax, Nantes, France.
¹¹ Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France.
¹² Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, Nantes, France.
¹³ Department of Ophthalmology, Semmelweis University, Budapest, Hungary.
¹⁴ European Vision Institute, Basel, Switzerland.
¹⁵ Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria.
¹⁶ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland. [email protected].
¹⁷ Department of Ophthalmology, University of Basel, Basel, Switzerland. [email protected].
¹⁸ Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary. [email protected].
¹⁹ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland. [email protected].
²⁰ Department of Ophthalmology, University of Basel, Basel, Switzerland. [email protected].

PMID: 39779923
DOI: 10.1038/s41591-024-03422-8

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 encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.Gly1961Glu). We optimized ABCA4 base editing in human models, including retinal organoids, induced pluripotent stem cell-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal explants and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in female nonhuman primates, with average editing of 75% of cones and 87% of RPE cells in vivo, which has the potential to translate to a clinical benefit. No off-target editing was detectable in human retinal explants and RPE/choroid explants. The high editing rates in primates show promise for efficient gene editing in other ocular diseases that are targetable by base editing.

Abstract

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