RESUMEN
Retinitis Pigmentosa (RP) is a mostly incurable inherited retinal degeneration affecting approximately 1 in 4000 individuals globally. The goal of this work was to identify drugs that can help patients suffering from the disease. To accomplish this, we screened drugs on a zebrafish autosomal dominant RP model. This model expresses a truncated human rhodopsin transgene (Q344X) causing significant rod degeneration by 7 days post-fertilization (dpf). Consequently, the larvae displayed a deficit in visual motor response (VMR) under scotopic condition. The diminished VMR was leveraged to screen an ENZO SCREEN-WELL REDOX library since oxidative stress is postulated to play a role in RP progression. Our screening identified a beta-blocker, carvedilol, that ameliorated the deficient VMR of the RP larvae and increased their rod number. Carvedilol may directly on rods as it affected the adrenergic pathway in the photoreceptor-like human Y79 cell line. Since carvedilol is an FDA-approved drug, our findings suggest that carvedilol can potentially be repurposed to treat autosomal dominant RP patients.
Asunto(s)
Animales Modificados Genéticamente , Conducta Animal/efectos de los fármacos , Enfermedades Genéticas Congénitas , Retinitis Pigmentosa , Rodopsina , Visión Ocular , Pez Cebra , Animales , Animales Modificados Genéticamente/genética , Animales Modificados Genéticamente/metabolismo , Línea Celular , Evaluación Preclínica de Medicamentos , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Humanos , Mutación , Células Fotorreceptoras Retinianas Bastones , Retinitis Pigmentosa/tratamiento farmacológico , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Rodopsina/genética , Rodopsina/metabolismo , Transgenes , Visión Ocular/efectos de los fármacos , Visión Ocular/inmunología , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
Zebrafish are a popular vertebrate model in drug discovery. They produce a large number of small and rapidly-developing embryos. These embryos display rich visual-behaviors that can be used to screen drugs for treating retinal degeneration (RD). RD comprises blinding diseases such as Retinitis Pigmentosa, which affects 1 in 4000 people. This disease has no definitive cure, emphasizing an urgency to identify new drugs. In this review, we will discuss advantages, challenges, and research developments in using zebrafish behaviors to screen drugs in vivo. We will specifically discuss a visual-motor response that can potentially expedite discovery of new RD drugs.