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Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):12489-12494. doi: 10.1073/pnas.1809432115. Epub 2018 Nov 16.

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

Author information

1
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom.
2
Renal Services, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, United Kingdom.
3
Laboratory of Hereditary Kidney Diseases, INSERM UMR 1163, Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
4
Electron Microscopy Research Services, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
5
Sunderland Eye Infirmary, Sunderland SR2 9HP, United Kingdom.
6
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom; colin.miles@newcastle.ac.uk john.sayer@newcastle.ac.uk.
7
National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne NE4 5PL, United Kingdom.

Abstract

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.

KEYWORDS:

Cep290; Joubert syndrome; antisense oligonucleotide therapy; ciliopathy; cystic kidney

PMID:
30446612
PMCID:
PMC6298104
DOI:
10.1073/pnas.1809432115
[Indexed for MEDLINE]
Free PMC Article

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