Although most heterozygous pathogenic variants in CRX are associated with autosomal dominant retinal degeneration, a homozygous c.268C> T (p.Arg90Trp) substitution and homozygous complete deletion of CRX have been reported to cause Leber congenital amaurosis.
In particular, the first gene therapy bioproduct for RPE65-associated Leber's congenital amaurosis, which was approved by the US Food and Drug Administration in 2017, has provided tremendous encouragement to the field of gene therapy.
Pathogenic variants in CRB1 lead to a huge variety of phenotypes ranging from milder forms of inherited retinal dystrophy, such as retinitis pigmentosa to more severe phenotypes such as Leber congenital amaurosis.
Currently, large sets of DNA samples are screened to identify patients with Leber's congenital amaurosis (LCA) carrying mutations in RPE65 as possible candidates for gene therapy trials.
Because of the early onset of disease in patients who have RP with PPRPE, we considered CRB1 to be a good candidate gene for Leber congenital amaurosis (LCA).
Ocular gene therapy with recombinant adeno-associated virus (AAV) has shown vector-mediated gene augmentation to be safe and efficacious in the retina in one set of diseases (retinitis pigmentosa and Leber congenital amaurosis (LCA) caused by RPE65 deficiency), with excellent safety profiles to date and potential for efficacy in several additional diseases.
Here we compared the impacts of two mutations in RPE65, E417Q identified in patients with Leber congenital amaurosis (LCA), and E417D on isomerohydrolase activity.
We hypothesize, from these animal models, that decreased levels of CRB2 in immature photoreceptors adjust retinitis pigmentosa because of the loss of CRB1 into Leber congenital amaurosis phenotype.
The success of gene therapy in the RPE65 form of Leber congenital amaurosis has provided a brilliant example of this hope; that a similar trial may become available to other patients and families burdened by genetic disease.
Mutations in human RPE65 cause Leber's congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness.