Gene

Genetic enhancement

Cell biology

Neuroscience

Retinal pigment epithelium

Biology

Genome editing

Retina

Retinitis pigmentosa

Retinal

Ophthalmology

CRISPR

Cis-trans-Isomerases

Biochemistry

Genetics

In vivo

Electroretinography

Isomerase

Retinal degeneration

Macular degeneration

RPE65

Medicine

Visual phototransduction

Peptidylprolyl isomerase

Nature Communications

Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting in early visual impairment. It is therefore crucial to develop a robust therapy that not only compensates for lost RPE65 function but also protects photoreceptors from further degeneration. Here, we show that in vivo correction of an Rpe65 mutation by adenine base editor (ABE) prolongs the survival of cones in an LCA mouse model. In vitro screening of ABEs and sgRNAs enables the identification of a variant that enhances in vivo correction efficiency. Subretinal delivery of ABE and sgRNA corrects up to 40% of Rpe65 transcripts, restores cone-mediated visual function, and preserves cones in LCA mice. Single-cell RNA-seq reveals upregulation of genes associated with cone phototransduction and survival. Our findings demonstrate base editing as a potential gene therapy that confers long-lasting retinal protection.

In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration