PRECLINICAL SCREENING OF A POTENTIALLY THERAPEUTIC COMPOUND TO TEST RESCUE OF RETINAL DEGENERATION IN A ZEBRAFISH MODEL OF USHER TYPE 1F

Abstract

Usher syndrome (USH) is a genetic disorder that affects 4 to 17 people per 100,000 worldwide. Usher syndrome type 1 (USH1), the most severe form of USH, is characterized by hearing and balance disorders at birth, and a progressive loss of vision beginning in childhood. Usher syndrome type 1F (USH1F), a subcategory of USH1, is caused by mutations in the PCDH15 gene. Mutations in PCDH15 that prematurely terminate the information encoded in the gene lead to truncated versions of the protocadherin-15 protein (PCDH15). This reduced or absent PCDH15 protein function leads to structural abnormalities in the hair cells of the inner ear and photoreceptors in the eye. We used a zebrafish model of USH1F to investigate whether hexafluoro, an antioxidant compound, can improve vision or retinal pathology in fish with impaired Pcdh15 protein function. We used an optokinetic response (OKR) assay to test whether hexafluoro-treated mutants showed improved vision compared to control fish, and examined photoreceptor cell integrity and survival in treated and untreated mutants. We found that hexafluoro improved visual function in USH1F mutant fish, and showed potential for reducing photoreceptor cell death. Our data indicate that hexafluoro has a stabilizing effect on retinal defects in zebrafish USH1F models, which are comparable to the early stages of human USH1F pathology, and provide proof of principle for expanding the effects of this and other drugs on zebrafish models of USH.