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<p>Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the <i>ABCA4</i> gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in <i>ABCA4</i> (c.5882G&gt;A, p.Gly1961Glu). We optimized <i>ABCA4</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月8日

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  • 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

摘要

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.