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Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model

Lookup NU author(s): Dr Simon RamsbottomORCiD, Dr Elisa MolinariORCiD, Dr Shalabh Srivastava, Sumaya Alkanderi, Laura Devlin, Dr Kathryn White, David Steel, Dr Colin Miles, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2018 National Academy of Sciences. All Rights Reserved. Genetic treatments of renal ciliopathies leading to cystic kidney disease would provide a real advance in current therapies. Mutations in CEP290 underlie a ciliopathy called Joubert syndrome (JBTS). Human disease phenotypes include cerebral, retinal, and renal disease, which typically progresses to end stage renal failure (ESRF) within the first two decades of life. While currently incurable, there is often a period of years between diagnosis and ESRF that provides a potential window for therapeutic intervention. By studying patient biopsies, patient-derived kidney cells, and a mouse model, we identify abnormal elongation of primary cilia as a key pathophysi-ological feature of CEP290-associated JBTS and show that antisense oligonucleotide (ASO)-induced splicing of the mutated exon (41, G1890*) restores protein expression in patient cells. We demonstrate that ASO-induced splicing leading to exon skipping is tolerated, resulting in correct localization of CEP290 protein to the ciliary transition zone, and restoration of normal cilia length in patient kidney cells. Using a gene trap Cep290 mouse model of JBTS, we show that systemic ASO treatment can reduce the cystic burden of diseased kidneys in vivo. These findings indicate that ASO treatment may represent a promising therapeutic approach for kidney disease in CEP290-associated ciliopathy syndromes.

Publication metadata

Author(s): Ramsbottom SA, Molinari E, Srivastava S, Silberman F, Henry C, Alkanderi S, Devlin LA, White K, Steel DH, Saunier S, Miles CG, Sayer JA

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2018

Volume: 115

Issue: 49

Pages: 12489-12494

Online publication date: 16/11/2018

Acceptance date: 02/04/2016

Date deposited: 18/12/2018

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences


DOI: 10.1073/pnas.1809432115

PubMed id: 30446612


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