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Lookup NU author(s): Dr Simon RamsbottomORCiD, Dr Elisa MolinariORCiD, Dr Shalabh Srivastava, Sumaya Alkanderi, Laura Devlin, Dr Kathryn White, Professor David SteelORCiD, 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).
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 pathophysiological 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.
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: National Academy of Sciences. Proceedings (PNAS)
Year: 2018
Volume: 115
Issue: 49
Pages: 12489-12494
Print publication date: 04/12/2018
Online publication date: 16/11/2018
Acceptance date: 19/10/2018
Date deposited: 08/01/2019
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://www.pnas.org/content/115/49/12489
DOI: https://doi.org/10.1073/pnas.1809432115
PubMed id: 30446612
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