Evaluation of Novel Enhancer Compounds in Gentamicin-Mediated Readthrough of Nonsense Mutations in Rett Syndrome

Author:

Wong Keit Men12ORCID,Wegener Eike3,Baradaran-Heravi Alireza4,Huppke Brenda12,Gärtner Jutta3ORCID,Huppke Peter12

Affiliation:

1. Department of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany

2. Center for Rare Diseases, Jena University Hospital, 07747 Jena, Germany

3. Department of Pediatrics and Adolescent Medicine, Division of Neuropediatrics, Pediatric Neurology University Medical Center Göttingen, Georg August University Göttingen, 37075 Göttingen, Germany

4. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver BC V6T 1Z3, Canada

Abstract

Rett syndrome (RTT), a severe X-linked neurodevelopmental disorder, is primarily caused by mutations in the methyl CpG binding protein 2 gene (MECP2). Over 35% RTT patients carry nonsense mutation in MECP2, making it a suitable candidate disease for nonsense suppression therapy. In our previous study, gentamicin was found to induce readthrough of MECP2 nonsense mutations with modest efficiency. Given the recent discovery of readthrough enhancers, CDX compounds, we herein evaluated the potentiation effect of CDX5-1, CDX5-288, and CDX6-180 on gentamicin-mediated readthrough efficiency in transfected HeLa cell lines bearing the four most common MECP2 nonsense mutations. We showed that all three CDX compounds potentiated gentamicin-mediated readthrough and increased full-length MeCP2 protein levels in cells expressing the R168X, R255X, R270X, and R294X nonsense mutations. Among all three CDX compounds, CDX5-288 was the most potent enhancer and enabled the use of reduced doses of gentamicin, thus mitigating the toxicity. Furthermore, we successfully demonstrated the upregulation of full-length Mecp2 protein expression in fibroblasts derived from Mecp2R255X/Y mice through combinatorial treatment. Taken together, findings demonstrate the feasibility of this combinatorial approach to nonsense suppression therapy for a subset of RTT patients.

Funder

The German Research Foundation

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference61 articles.

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