AAV-Mediated Gene Therapy for CRB1-Hereditary Retinopathies

Abstract

Variations in the Crumbs homolog-1 (CRB1) gene lead to autosomal recessive retinal dystrophies such as early-onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). No treatment is yet available for these patients. Adeno-associated virus (AAV) mediated gene therapy for hereditary retinal diseases holds great promise proven by the large number of active clinical trials. We here summarized the knowledge about the localization and function of CRB1 in the retina and the main pathological features resulting from loss of CRB1 function in humans and in rodents. This know-how is being applied to design and develop AAV gene therapy vectors for the treatment of CRB1-Hereditary retinopathies. Knowing which cell types express the CRB proteins, the possible redundancy of function between CRB1 and CRB2, and the AAV tropism in the human retina, will allow us to rationalize about the AAV capsid, promoter and route of administration that should be used in the AAV vector in order to efficiently and specifically deliver CRB1 or CRB2 into the human retina.

Tissue engineering of the retina: from organoids to microfluidic chips

“…Since the successful results of the first approved ocular gene therapy, a gene supplementation of RPE65 in patients with Leber congenital amaurosis, 72 – 74 many more gene therapies are currently in the clinical phase of development for the treatment of inherited retinal dystrophies including RP, 75 – 78 age-related macular 79 or Leber hereditary optic neuropathy, 80 among others. 81 , 82 Although gene therapies are a promising clinical tool, there are limitations regarding the diseases they can be used to treat, with outcomes dependent upon the stage and progression of the disease. Gene therapy strategies that restore function within the retina, are limited only to those patients still presenting functional photoreceptors.…”