Patients and animal models of CNG[beta]1-deficient retinitis pigmentosa support gene augmentation approach

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel [beta] 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; how...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-01, Vol.128 (1), p.190
Main Authors: Petersen-Jones, Simon M, Occelli, Laurence M, Winkler, Paige A, Lee, Winston, Sparrow, Janet R, Tsukikawa, Mai, Boye, Sanford L, Chiodo, Vince, Capasso, Jenina E, Becirovic, Elvir, Schon, Christian, Seeliger, Mathias W, Levin, Alex V, Michalakis, Stylianos, Hauswirth, William W, Tsang, Stephen H
Format: Article
Language:English
Subjects:
Analysis
Biological markers
Development and progression
Genetic aspects
Mutation
Phenotypes
Retinitis pigmentosa
Online Access:Get full text
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Summary:Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel [beta] 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNG[beta]1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI95161.