huAIPL1-FLAG-W278* Mouse

Leber congenital amaurosis (LCA) is a severe inherited blinding retinal disease, accounting for approximately 5% of all inherited retinal diseases. Its global prevalence is approximately 1/80,000 to 1/30,000, and it is one of the blinding eye diseases that causes rapid visual decline after birth. LCA is the earliest-onset and most severe inherited retinal dystrophy. In patients, cone and rod photoreceptor function is completely lost at birth or within the first year of life, resulting in congenital blindness in infants and following an autosomal recessive inheritance pattern. LCA has been classified into at least 17 subtypes, among which AIPL1 gene mutations cause LCA type 4, accounting for approximately 5%–10% of LCA cases [1-2]. AIPL1 encodes aryl hydrocarbon receptor-interacting protein-like 1, which acts as an HSP90 co-chaperone in retinal photoreceptors and is essential for the proper assembly of the rod phototransduction cascade. The truncated protein produced by the W278* mutation lacks the C-terminal TPR domain and is unable to bind HSP90, leading to impaired PDE6 folding and cGMP accumulation, which in turn causes photoreceptor apoptosis and ultimately results in LCA4 [3-6]. Currently, no approved therapy is available for LCA4. Readthrough drugs targeting nonsense mutations have shown potential to restore full-length protein in patient-derived retinal organoids, and adenine base editing has also achieved correction of such variants in patient cell and organoid models [7-8]. Furthermore, AIPL1 variants can cause severe retinal dystrophy with childhood onset, and missense variants that retain partial protein function result in relatively milder phenotypes [9].

The huAIPL1-FLAG-W278* mouse is a humanized model constructed by gene editing technology. The sequence of the endogenous mouse Aipl1 gene from the start codon to the stop codon is replaced with the sequence of the human AIPL1 gene from the start codon to the stop codon, while the p.W278* (TGG to TGA) mutation is introduced into exon 6 of the human AIPL1 gene and a FLAG tag is inserted downstream of the start codon. This model can be used for studying the pathogenesis of LCA4 and the process of photoreceptor degeneration, as well as for screening, development, and preclinical in vivo evaluation of AIPL1-targeted therapies.