Abstract
Once considered science fiction, gene therapy is rapidly becoming scientific reality, targeting a growing number of the approximately 250 genes linked to hereditary retinal disorders such as retinitis pigmentosa and Leber's congenital amaurosis. Powerful new technologies have emerged, leading to the development of humanized models for testing and screening these therapies, bringing us closer to the goal of personalized medicine. These tools include the ability to differentiate human induced pluripotent stem cells (iPSCs) to create a “retina-in-a-dish” model and the self-formed ectodermal autonomous multi-zone, which can mimic whole eye development. In addition, highly specific gene-editing tools are now available, including the CRISPR/Cas9 system and the recently developed homology-independent targeted integration approach, which allows gene editing in non-dividing cells. Variants in the CRB1 gene have long been associated with retinopathies, and more recently the CRB2 gene has also been shown to have possible clinical relevance with respect to retinopathies. In this review, we discuss the role of the CRB protein complex in patients with retinopathy. In addition, we discuss new opportunities provided by stem cells and gene-editing tools, and we provide insight into how the retinal therapeutic pipeline can be improved. Finally, we discuss the current state of adeno-associated virus-mediated gene therapy and how it can be applied to treat retinopathies associated with mutations in CRB1.
Highlights
Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
Gene therapy is rapidly becoming scientific reality, targeting a growing number of the approximately 250 genes linked to hereditary retinal disorders such as retinitis pigmentosa and Leber’s congenital amaurosis
Variants in the CRB1 gene have long been associated with retinopathies, and more recently the CRB2 gene has been shown to have possible clinical relevance with respect to retinopathies
Summary
2003; Cordovez et al, 2015; Talib et al, in press den Hollander et al, 1999; Lotery et al, 2001 Heckenlively, 1982. Both Crb and Crb in their retinal progenitor cells During development, these Crb1Crb double-knockout mice have dysregulated apical-basal polarity in the retina, altered retinal progenitor cell proliferation, and reduced downstream CRB signaling, including dysregulation of YAP (Yes-associated protein). These Crb1Crb double-knockout mice have dysregulated apical-basal polarity in the retina, altered retinal progenitor cell proliferation, and reduced downstream CRB signaling, including dysregulation of YAP (Yes-associated protein) These findings highlight the essential role that the CRB (Crumbs) complex plays in normal retinal development (Pellissier et al, 2013). More than 230 pathogenic variants have been identified in the CRB1 gene (see http://exac.broadinstitute.org/transcript/ ENST00000367400 and http://databases.lovd.nl/shared/variants/ CRB1) It is not currently clear why a given variant can lead to either early-onset LCA or RP within the disease spectrum. CRB3 mRNA has been found in the macula and peripheral retina, the CRB3 gene has yet to be linked to retinal disease (Pellissier et al, 2014b)
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