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Fischer, M. Dominik, MD, DPhil*,†,‡,§; Ochakovski, G. Alex, MD*,†; Beier, Benjamin, BSc; Seitz, Immanuel P.*,†; Vaheb, Yousof, MD*; Kortuem, Constanze, MD*; Reichel, Felix F. L.*,†; Kuehlewein, Laura, MD*; Kahle, Nadine A., PhD; Peters, Tobias, MD; Girach, Aniz, MD; Zrenner, Eberhart, MD*,†; Ueffing, Marius, PhD; MacLaren, Robert E., MD, DPhil§,¶,**,††; Bartz-Schmidt, KarlUlrich, MD*; Wilhelm, Barbara, MD

doi: 10.1097/IAE.0000000000002360
Original Study: PDF Only

Purpose: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1).

Methods: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51–60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 1011 genome particles during vitrectomy. Twelve-month data are reported.

Results: In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (−4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of −2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (−36.1 [66.9] deg2) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure.

Conclusion: Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained.

Six patients with choroideremia underwent gene therapy with AAV2-REP1. At 12 months, 5/6 patients report maintenance or improvement in visual acuity and improvements in mean retinal sensitivity, peak retinal sensitivity, and gaze fixation area. Safety outcomes are consistent with vitrectomy. The study is ongoing.

*University Eye Hospital, Centre for Ophthalmology, Tübingen, Germany;

Institute for Ophthalmic Research, Centre for Ophthalmology, Tübingen, Germany;

STZ Eyetrial at the Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany;

§Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom;

Nightstar Therapeutics, London, United Kingdom;

**Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom; and

††Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.

Reprint requests: M. Dominik Fischer, MD, DPhil, Centre for Ophthalmology, Elfriede-Aulhorn-Straße 7, Tübingen 72076, Germany; e-mail:

Tistou und Charlotte Kerstan Stiftung, Tübingen.

None of the authors has any financial/conflicting interests to disclose.

Authors have disclosed any conflicts of interest in the Authorship Responsibility, Financial Disclosure, and Copyright Transfer form Identifier: NCT02671539.

© 2019 by Ophthalmic Communications Society, Inc.