Efficacy and Safety of Retinal Gene Therapy Using Adeno-Associated Virus Vector for Patients With Choroideremia: A Randomized Clinical Trial

Abstract

Importance: Choroideremia (CHM) is a rare, degenerative, genetic retinal disorder resulting from mutation of the CHM gene, leading to an absence of functional ras-associated binding escort protein 1 (REP1). There is currently no approved treatment for CHM.

Objective: To assess the safety and efficacy of retinal gene therapy with an adeno-associated virus vector (AAV2) designed to deliver a functional version of the CHM gene (AAV2-REP1) for treatment of patients with choroideremia.

Design, setting, and participants: Tübingen Choroideremia Gene Therapy (THOR) was a single-center, phase 2, open-label randomized clinical trial. Data were collected from January 11, 2016, to February 26, 2018. Twenty-four-month data are reported for 6 men with a molecularly confirmed diagnosis of CHM. Intention-to-treat analysis was used.

Interventions: Patients received AAV2-REP1 by a single, 0.1-mL subretinal injection of 1011 genome particles during vitrectomy into 1 eye randomly assigned to receive treatment.

Main outcomes and measures: Primary end point was change in best-corrected visual acuity (BCVA) on the Early Treatment Diabetic Retinopathy Study chart from baseline to month 24 in the treated eye vs the control eye. Secondary end points included microperimetry variables, change in fundus autofluorescence, and spectral-domain optical coherence tomographic evaluations from baseline to month 24 in the treated eye vs the control eye.

Results: On enrollment, the mean (SD) age of the 6 men included in the study was 54.9 (4.1) years. The mean (SD) BCVA score was 60.3 (13.4) (approximately 20/63 Snellen equivalent) in the study eyes and 69.3 (20.6) (approximately 20/40 Snellen equivalent) in the control eyes. At 24 months, the BCVA change was 3.7 (7.5) in the treated eyes and 0.0 (5.1) in the control eyes (difference, 3.7; 95% CI, -7.2 to 14.5; P = .43). Mean change in retinal sensitivity was 10.3 (5.5) dB in the treated eyes and 9.7 (4.9) dB in the control eyes (difference, 0.6; 95% CI, -10.2 to 11.4; P = .74). A total of 28 adverse events were reported; all were consistent with the surgical procedure (eg, conjunctival hyperemia, foreign body sensation), and none were regarded as severe.

Conclusions and relevance: Among 6 participants, gene therapy with AAV2-REP1 was associated with maintenance or improvement of visual acuity, although no significant difference was found from control eyes. All safety issues were associated with the surgical procedure and none were judged severe. Continued investigations could more precisely define the efficacy and safety of gene therapy with AAV2-REP1 in CHM.

Trial registration: ClinicalTrials.gov identifier: NCT02671539.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fischer reported receiving nonfinancial support from Nightstar Therapeutics during the conduct of the study, grants and personal fees from Casebia Therapeutics, and personal fees from Nightstar Therapeutics, Novartis, Sanofi, Adelphi Values, EyeServ, and Retina Implant outside the submitted work. In addition, Dr Fischer reported having a patent to WO2017/042584 pending, licensed, and with royalties paid. Mr Beier reported receiving grants from Tistou and Charlotte Kerstan Foundation during the conduct of the study. Dr Vaheb reported receiving grants from Kerstan Foundation during the conduct of the study. Dr Kortuem reported receiving grants from Nightstar Therapeutics during the conduct of the study. Dr Kahle reported receiving grants from Tistou and Charlotte Kerstan Foundation during the conduct of the study. This work was supported by the Tistou and Charlotte Kerstan Foundation by a grant to the University of Tübingen. Dr MacLaren reported receiving grants and personal fees from Nightstar Therapeutics outside the submitted work. In addition, Dr MacLaren reported having a patent for choroideremia gene therapy issued and licensed. Dr Bartz-Schmidt reported receiving personal fees and nonfinancial support from Retina Implant outside the submitted work. Dr Wilhelm reported receiving grants from Tistou and Charlotte Kerstan Foundation during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Flowchart of the Study

Figure 2.. Change in Visual Function Outcomes From Baseline to Month 24 in Treated and Control Eyes of All Patients

Mean changes in best-corrected visual acuity (BCVA) as Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (A), sensitivity (B), and peak sensitivity (C). Error bars represent 95% CIs.

Figure 3.. Mean Change in Anatomic End Points From Baseline in the 24 Months Following Surgery

Changes in treated (A) and untreated control (B) eyes. Error bars represent 95% CIs. EZ indicates ellipsoid zone; FAF, fundus autofluorescence.