Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach
Simon M. Petersen-Jones, … , William W. Hauswirth, Stephen H. Tsang
Simon M. Petersen-Jones, … , William W. Hauswirth, Stephen H. Tsang
Published January 2, 2018; First published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):190-206. https://doi.org/10.1172/JCI95161.
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Categories: Research Article Ophthalmology

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach

Abstract

Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 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 CNGβ1-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.

Authors

Simon M. Petersen-Jones, Laurence M. Occelli, Paige A. Winkler, Winston Lee, Janet R. Sparrow, Mai Tsukikawa, Sanford L. Boye, Vince Chiodo, Jenina E. Capasso, Elvir Becirovic, Christian Schön, Mathias W. Seeliger, Alex V. Levin, Stylianos Michalakis, William W. Hauswirth, Stephen H. Tsang

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Figure 5

Cone function slowly declines with age in the Cngb1–/– dog.

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Cone function slowly declines with age in the Cngb1–/– dog. (A) Photopic...
(A) Photopic single-flash ERG tracings in response to the following stimuli in the light-adapted eye present on a background of 30 cd/m2: –0.4, 0.0, 0.4, 0.9, 1.4, and 1.9 log cds/m2 (top to bottom tracings), and at the bottom, a photopic 33-Hz flicker response at 0.4 log cds/m2. (B and C) Change in the mean (± SD) photopic a-wave (B) and b-wave (C) amplitudes in response to the 0.4 log cds/m2 stimulus with age. The mean photopic a-wave amplitude for Cngb1–/– dogs was significantly lower at 42 and 66 months of age (P < 0.05, Student’s t test). The mean photopic b-wave was significantly reduced at 66 months of age (P < 0.01, Student’s t test). n = 2 Cngb1–/– dogs at each time point; n = 3 controls at 14 and 36 months; and n = 2 controls at 72 months. (D and E) Results of vision testing showing the percentage of dogs that made the correct exit choice (D) and the time taken to exit (E). At all ages tested, the affected dogs had reduced visual function at the lowest light level. Bright light vision was maintained in all age groups tested. Control dogs: n = 6; Cngb1–/– dogs: n = 3 for 4-month-old and 12- to 24-month-old dogs and n = 4 for 36- to 48-month-old dogs.