Correcting a patient-specific Rhodopsin mutation with adenine base editor in a mouse model.

Abstract

Genome editing offers a great promise to treating human genetic diseases. To assess the genome editing mediated therapeutic effects in vivo, an animal model is indispensable. While, the genomic disparities between mice and humans often impede the direct clinical application of genome editing mediated treatments using conventional mouse models. Thus, the generation of a mouse model with a humanized genomic segment containing a patient-specific mutation is highly sought after for translational research. In this study, we successfully developed a knock-in mouse model for autosomal dominant retinitis pigmentosa (adRP), designated as hT17M knock-in, which incorporates a 75-nucleotide DNA segment with the T17M mutation (Rhodopsin-c.C50T; p.T17M). This model demonstrated significant reductions in electroretinogram (ERG) amplitudes and exhibited disruptions in retinal structure. Subsequently, we administered an adeno-associated virus (AAVs) carrying an adenine base editor (ABE) and a single-guide RNA (sgRNA) specifically targeting the T17M mutation, achieving a peak correction rate of 39.7% at the RNA level and significantly improving retinal function in ABE-injected mice. These findings underscore that the hT17M knock-in mouse model recapitulates the clinical features of adRP patients as well as exhibits therapeutic effects with ABE-mediated treatments. It offers a promising avenue for the development of gene-editing therapies for retinitis pigmentosa.