Leber’s congenital amaurosis (LCA) is one of the major inherited causes of childhood blindness. Mutations in the cone-rod homeobox (CRX) gene result in severe dominant retinopathies and can be responsible for LCA. CRX is a transcription factor essential for normal photoreceptor development and survival. The CrxRdy cat has a spontaneous frameshift mutation in Crx and represents a model for Class III CRX mutations where the mutant CRX allele binds DNA but fails to transactivate it. The CrxRdy cat model is valuable for investigating disease mechanisms as well as potential therapy development. In this model, early disease stages in the heterozygous cat (CrxRdy/+) mimic severe Leber’s congenital amaurosis. This is characterized by a dominant negative effect of the mutant Crx mRNA/protein over the wild-type mRNA/protein. This study fully investigated the early phenotype as well as the timing and extent of retinal remodeling during retinal degeneration. There is early halting of photoreceptor development coupled with over expression of the mutant Crx allele, accumulation of abnormally high mutant Crx protein levels, resulting in markedly impaired visual function followed by retinal degeneration. During the late stages of the disease, extensive inner retinal remodeling occurred with some retinal pigmentary epithelium (RPE) degeneration in the area centralis (macula-like high retinal acuity region of the feline retina) and also vascular remodeling. The homozygous cat (CrxRdy/Rdy) had a different phenotype with halting of photoreceptor development at an earlier stage resulting in complete blindness and total lack of photoreceptor function. This was followed by a slower photoreceptor degeneration and extensive retinal remodeling that differed from that of the heterozygote cat. Additionally, there was a marked increase in globe size with a severe alteration in refraction. There is currently no treatment for dominant negative LCA diseases. Yet, the investigation findings on CrxRdy/+ cat model and the similarities between the feline eye and the human eye with the presence of a macula-like region make this feline model valuable for preclinical testing of therapies for dominant CRX diseases. The detailed phenotyping sheds light on the therapeutic approach needed. Prior to photoreceptor degeneration, a therapeutic approach aiming to restore function to endogenous photoreceptors would need to increase the expression levels of the wild-type allele over the mutant transcript. Following photoreceptor degeneration, therapeutic approaches to replace photoreceptors or to activate light-induced responses in other retinal neurons would need to be performed before retinal remodeling and neuronal cell loss become too extensive. Trial therapy using a gene augmentation approach showed some promise to improve the phenotype but requires further optimization.The CrxRdy cat is a valuable model for Class III CRX mutations, RPE degeneration and deprivation myopia mechanism, and therapy development.
Read
