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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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 2

Progressive AF ring constriction and photoreceptor layer thinning in affected patients homozygous and compound heterozygous for CNGB1 mutations.

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Progressive AF ring constriction and photoreceptor layer thinning in aff...
Affected patients homozygous for CNGB1: patients 1 and 2 (p.Phe1051Leufs*12); affected patient heterozygous for CNGB1: patient 6 (p.Leu849Profs*3, p.Lys175Glnfs*4). (A) FAF imaging (488-nm) of the right eye in each patient revealed the inner and outer border (white arrows) of a progressively constricting region (ring), delineating the centrally preserved area of retinal function. (B) Retinal schematic illustrating the constriction size (mm2) and shape of the centrally preserved region over various time intervals (insets): after 60 months in patient 1 (red) and patient 2 (blue) and 20 months in patient 6 (green). (C) Color-coded maps of total REC+ thickness after 60 months in patients 1 and 2 and after 20 months in patient 6 from a segmented macular SD-OCT scan within the position of the retina enclosed in the red rectangle (upper right inset). The right eye of each patient is shown, where white on the color scale (>125 μm) denotes the range of REC+ thickness in healthy eyes. REC+ thickness is defined as all visible layers between the inner nuclear layer–ONL (INL-ONL) complex and the Bruch’s membrane–choroidal interface (SD-OCT, inset). BM, basement membrane.