HumanCRB1-Associated Retinal Degeneration: Comparison with therd8 Crb1-Mutant Mouse Model

There has been longstanding scientific interest in Crumbs proteins, originating from discoveries in Drosophila; in mammals, there are several homologues of Crumbs (reviewed in Ref. 1). CRB1 is thought to be expressed in Muller glial (MG) cells and localizes at a subapical region near intercellular adherens junctions between photoreceptors and MG cells at the outer limiting membrane (OLM). Mutations in the CRB1 gene cause an autosomal recessive early-onset retinal degeneration characterized by abnormal retinal organization and severe visual loss.2–7 Results to date in patients with CRB1-associated retinal degenerations (CRB1-RD), taken together with findings in experimental animals, support the conjecture that CRB1 mutations result in retinal maldevelopment and progressive degeneration.5,8 There is also experimental evidence supporting a role for CRB1 in the maintenance of photoreceptor integrity.8,9 Major progress was made recently when gene replacement therapy for another recessive early-onset retinal degeneration, the RPE65 form of Leber congenital amaurosis (LCA), was shown to be safe and efficacious in early-phase clinical trials (reviewed in Ref. 10). One of the important challenges facing the field of retinal degenerations is how to expand the recent gene therapy success in RPE65-LCA to dozens of other molecular forms of retinitis pigmentosa (RP) and LCA with different pathophysiological mechanisms. It remains unclear whether CRB1-RD patients are candidates for such emerging therapies. In this work we used psychophysics, retinal imaging, and cortical imaging to increase understanding of the disease effects associated with CRB1-RD, with the ultimate goal of assessing the relevance of treatment strategies to this group of patients. In addition, we made a side-by-side comparison of the human retinopathy with that of the retinal disease in the rd8 mouse, a naturally occurring Crb1 mutant. The results of this comparison are a key issue for proof-of-concept studies.