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 8

Retinal structure is preserved in gene therapy–treated retinal regions in Cngb1–/– dogs.

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Retinal structure is preserved in gene therapy–treated retinal regions i...
(A) SD-OCT cross-sectional images of the retinal region of an AAV5-hGRK1-cCgnb1–treated Cngb1–/– dog showing preservation of the retinal layers. In addition to ONL preservation, the ELM, EZ, and IZ appear to have better definition compared with untreated Cngb1–/– dogs. A WT control retina is shown for comparison. IR, inner retina; TR, total retina. (B) Plot of the mean thickness of the REC+ layer with age in Cngb1–/– treated retinae (n = 2) compared with Cngb1–/– untreated and unaffected dog retinae. The first time point of the Cngb1–/– measurement was 1 month after treatment. The untreated Cngb1–/– retina had a progressive, age-related decline in thickness. The treated eyes showed an initial decline in thickness of the REC+, like the untreated eyes, but then plateaued to remain significantly thicker than the REC+ layer of the untreated eye (P = 0.019, 2-tailed Student’s t test, 17–18 months of age). n = 3 untreated Cngb1–/– dogs. Data represent the mean ± SD. (C) FAF cSLO imaging of a treated eye 23 months after injection. The noninjected retinal region had a higher level of AF than did the treated (injected) region. Heatmap shows REC+ layer thickness preservation in the treated area of the same eye. (D) Cross-sectional SD-OCT images across the junction between injected and noninjected areas of the same eye as in C, showing a thinning of the ONL in the noninjected area (boundary is indicated by a white arrow). Also note the better definition of the ELM zone, the EZ, and the IZ zone on the image in the injected region. IHC image of the same region shows that Cngb1 expression stopped abruptly at the edge of the injected area (white arrow). Scale bars: 100 μm (A), 200 μm (D, top), and 100 μm (D, bottom).