Promising and delivering gene therapies for vision loss

Abstract

The maturity in our understanding of the genetics and the pathogenesis of disease in degenerative retinal disorders has intersected in past years with a novel treatment paradigm in which a genetic intervention may lead to sustained therapeutic benefit, and in some cases even restoration of vision. Here, we review this prospect of retinal gene therapy, discuss the enabling technologies that have led to first-in-human demonstrations of efficacy and safety, and the road that led to this exciting point in time.

Retinal gene delivery by adeno-associated virus (AAV) vectors: Strategies and applications

“…Various non-viral and viral vector systems have been evaluated for retinal gene transfer, including nanoparticles, lentivirus, adenovirus, and adeno-associated virus (AAV). AAVs have been proved to be the most suitable vectors for efficient and long-term expression in retinal cells [1][2][3]. Naturally occurring AAVs are very efficient in transducing photoreceptors, Müller glia, retinal pigment epithelial (RPE) cells or RGCs.…”

Gene Therapy for Blinding Pediatric Eye Disorders

“…Recombinant AAV is the most widely used vector for ocular gene delivery because of its ability to transduce efficiently in vivo various retinal cell types. Six different serotypes of AAV are currently used with different serotypes preferentially transfecting different layers of the retina; modifications of viral capsids can also direct transfection to specific retinal cell types [6].…”

“…However, adenovirus and lentivirus do not have the same safety profile as AAV, and nanoparticles are still unproven in clinical trials. Some viral vectors, such as lentivirus, insert the delivered gene into the genetic make-up of the cell rather than just directing production of its product in the nucleus [6]. Insertion into the host genome is not without risk; the location of insertion cannot be completely controlled, making the chance of altering nearby genes, including genes capable of causing cancer or other disorders, a concern.…”

Novel Methodology for Creating Macaque Retinas with Sortable Photoreceptors and Ganglion Cells

“…Conversely, AAV-mediated gene supplementation has been used to correct phenotypes in a myriad of retinal disease models (Boye et al, 2013; Carvalho and Vandenberghe, 2015; Schön et al, 2015). The establishment of AAV serotype and promoter combinations capable of restricting transgene expression to photoreceptors has been further extended to non-human primates (NHP; Vandenberghe et al, 2011, 2013; Boye et al, 2012; Ramachandran et al, 2016) and can be used in conjunction with a separate method that fluorescently labels retinal ganglion cells (RGCs).…”