Gene Therapy Rescues Retinal Degeneration in Receptor Expression-Enhancing Protein 6 Mutant Mice

Abstract

Hereditary retinal dystrophy is clinically defined as a broad group of chronic and progressive disorders that affect visual function by causing photoreceptor degeneration. Previously, we identified mutations in the gene encoding receptor expression-enhancing protein 6 (REEP6), in individuals with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with biallelic REEP6 mutations, a missense mutation over a frameshift mutation. In this study, we generated Reep6 compound heterozygous mice, Reep6, which mimic the patient genotype and recapitulate the early-onset retinal degeneration phenotypes observed in the individual with RP. To determine the feasibility of rescuing the Reep6 mutant phenotype via gene replacement therapy, we delivered Reep6.1, the mouse retina-specific isoform of REEP6, to photoreceptors of Reep6 mutant mice on postnatal day 20. Evaluation of the therapeutic effects 2 months posttreatment showed improvements in the photoresponse as well as preservation of photoreceptor cells. Importantly, guanylyl cyclase 1 (GC1) expression was also restored to the outer segment after treatment. Furthermore, rAAV8-Reep6.1 single treatment in Reep6 mutant mice 1 year postinjection showed significant improvements in retinal function and morphology, suggesting that the treatment is effective even after a prolonged period. Findings from this study show that gene replacement therapy in the retina with rAAV overexpressing Reep6 is effective, preserving photoreceptor function in Reep6 mutant mice. These findings provide evidence that rAAV8-based gene therapy can prolong survival of photoreceptors in vivo and can be potentially used as a therapeutic modality for treatment of patients with RP.

AAV8-Mediated Gene Therapy Rescues Retinal Degeneration Phenotype in a Tlcd3b Knockout Mouse Model

“…Among the various serotypes, a tyrosine-capsid mutant adeno-associated virus (AAV) vector plasmid, AAV8(Y733F), has been studied extensively to achieve high transduction efficiency, more rapid transgene expression, cell transduction specificity, and stable and long-term expression in photoreceptor cells. 26 , 27 , 33 – 35 As expected, the gene therapy significantly improved photoreceptor function and preservation of photoreceptor cells over a course of 1 year upon expression of rAAV8-Tlcd3b in the mutant retina. Consistent with the idea that TLCD3B is a ceramide synthase, mass spectrometry analyses of the mutant retina indicate the reduction of C16-, C18-, and C20-ceramides in the retina, which is restored by rAAV8-Tlcd3b expression.…”

The Clinical and Biological Effects of Receptor Expression-Enhancing Protein 6 in Tongue Squamous Cell Carcinoma

“…In addition, REEP6 with a novel nonsense variant was found to be associated with a sporadic rod-cone dystrophy case [18]. Interestingly, REEP6 gene therapy could rescue retinal degeneration in REEP6 mutant mice [19]. REEP6 also regulates adrenergic signal transduction in adipocytes, and its inactivation causes obesity-related metabolic dysfunction [6].…”

Identification of the Transcriptional Biomarkers Panel Linked to Pathological Remodelling of the Eye Tissues in Various HD Mouse Models

“…In HD mouse models, this gene was also found here to be significantly down-regulated at the symptomatic and end-stages, in the R6/1, R6/2, and HdhQ150 mice. Interestingly, rescuing the Reep6 mutant phenotype via gene replacement therapy showed significant improvements in the photoresponse and preserved photoreceptor cells [53]. In contrast, the Fabp7 gene has been found to be significantly up-regulated in HD mouse models.…”