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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

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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 1

Spectrum of disease severity in patients with CNGB1-associated RP.

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Spectrum of disease severity in patients with CNGB1-associated RP.
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Color fundus montages and corresponding AF images of the left eye of patient 1 (p.Phe1051Leufs*12 homozygous) (A), patient 6 (p.Leu849Profs*3; p.Lys175Glnfs*4) (B), and the right eyes of patient 7 (p.Cys632*; p.Phe1051Leufs*12) (C) and patient 8 (p.Arg762Cys homozygous), illustrating typical presentations of RP features: (B–D) waxy pallor of the optic disc, severe attenuation of the retinal vasculature (white arrowheads), and bone-spicule pigment clumping in the mid-periphery (insets). (A) The left macula of patient 1 (p.Phe1051Leufs*12 homozygous) shows largely unremarkable features for retinal degeneration. REC+ thickness is defined as all visiblelayers between the inner nuclear layer-outer nuclear layer (INL/ONL) complex and the Bruch’s membrane-choroidal (BM/Choroid) interface.
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Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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