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.
