RNA-based therapies in animal models of Leber congenital amaurosis causing blindness
| Autor: | Cheryl Y. Gregory-Evans, Kevin Gregory-Evans, Xianghong Shan, Xia Wang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
genetic structures Blindness business.industry RNA General Medicine Bioinformatics medicine.disease Leber congenital amaurosis eye diseases Ataluren 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Animal model chemistry medicine sense organs business 030217 neurology & neurosurgery |
| Zdroj: | Precision Clinical Medicine. 3:113-126 |
| ISSN: | 2516-1571 2096-5303 |
| Popis: | Leber congenital amaurosis (LCA) is a severe, genetically heterogeneous recessive eye disease in which ~ 35% of gene mutations are in-frame nonsense mutations coding for loss-of-function premature termination codons (PTCs) in mRNA. Nonsense suppression therapy allows read-through of PTCs leading to production of full-length protein. A limitation of nonsense suppression is that nonsense-mediated decay (NMD) degrades PTC-containing RNA transcripts. The purpose of this study was to determine whether inhibition of NMD could improve nonsense suppression efficacy in vivo. Using a high-throughput approach in the recessive cep290 zebrafish model of LCA (cep290;Q1223X), we first tested the NMD inhibitor Amlexanox in combination with the nonsense suppression drug Ataluren. We observed reduced retinal cell death and improved visual function. With these positive data, we next investigated whether this strategy was also applicable across species in two mammalian models: Rd12 (rpe65;R44X) and Rd3 (rd3;R107X) mouse models of LCA. In the Rd12 model, cell death was reduced, RPE65 protein was produced, and in vivo visual function testing was improved. We establish for the first time that the mechanism of action of Amlexanox in Rd12 retina was through reduced UPF1 phosphorylation. In the Rd3 model, however, no beneficial effect was observed with Ataluren alone or in combination with Amlexanox. This variation in response establishes that some forms of nonsense mutation LCA can be targeted by RNA therapies, but that this needs to be verified for each genotype. The implementation of precision medicine by identifying better responders to specific drugs is essential for development of validated retinal therapies. |
| Databáze: | OpenAIRE |
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