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

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 essential. While, due to the genome difference between mice and human, genome editing-based treatment developed with knock-out mouse models or even single-nucleotide mutation knock-in mouse models usually ca not be directly translated into the clinic. Thus, mouse disease model carrying DNA fragments and harboring an exact mutation from the patients at the corresponding loci is highly desired. Here we generated a knock-in mouse model of autosomal dominant retinitis pigmentosa (adRP), harboring a 75nt DNA fragment from the adRP patient, which was one of the most frequently reported disease-causative mutation (Rhodopsin-c.C50T; p.T17M). We observed that the amplitudes of electroretinogram (ERG) in knock-in mice were significantly decreased and the structure of retina was disrupted. Conversely, following the injection of adeno-associated virus (AAV) expressing adenine base editor (ABE) and sgRNA targeting the mutation to correct the pathogenic mutation, we found that the ABE-treated mice displayed improved retinal functions. It illustrated that the T17M-fragment knock-in mouse model recapitulates the clinical manifestations of adRP patients and the therapeutic effects of ABE mediated treatment of inherited retinal diseases.