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 November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):190-206. https://doi.org/10.1172/JCI95161.
View: Text | PDF
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

×

Figure 3

Cngb1–/– mice show a progressive loss of photoreceptor structure and function.

Options: View larger image (or click on image) Download as PowerPoint
Cngb1–/– mice show a progressive loss of photoreceptor structure and fu...
(A) Age-related loss of the REC+ layer in Cngb1–/– mice compared with WT mice, as measured by SD-OCT imaging. The colored vertical bars indicate the ages at which photopic ERG b-wave amplitudes were measured in C (mean of n = 4–6 for each time point). (B) IHC with a cone marker (cone arrestin) showing morphologically affected but still-persisting cones after advanced thinning of the ONL (representative images from 3 mice). Scale bar: 25 µm. (C) Photopic cone b-wave amplitudes of Cngb1–/– mice plotted against stimulus strength at 2, 6, and 8 months of age (mean of 4 for each time point). Data represent the mean ± SD. PW8, postnatal week 8; PW26, postnatal week 26; PW35, postnatal week 35.