Efficacy and Safety of Retinal Gene Therapy Using Adeno-Associated Virus Vector for Patients With Choroideremia

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 10 11 genome particles during vitrectomy into 1 eye randomly assigned to receive treatment. MAIN OUTCOMES AND MEASURESPrimary 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. RESULTSOn 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.

Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) in Patients with Choroideremia

“…This study used an adeno-associated virus vector (AAV2) to deliver a functional version of CHM to affected patients (AAV2-REP1). 51 Patients who received treatment showed general improvement of visual acuity with a mean gain of 3.7 letters on the BCVA ETDRS score and a significant reduction in the rate of retinal degeneration compared to untreated controls. Employing gene therapy approaches in conjunction with FLIO imaging in patients with CHM could show great potential.…”

“…47,50 Because CHM is a slowly progressive monogenic disease, this allows potential gene therapy initiatives a window of intervention to target the many pathological effects of disease. One study employed by Fischer and coworkers 51 was a phase 2 randomized clinical trial that included six patients with CHM. This study used an adeno-associated virus vector (AAV2) to deliver a functional version of CHM to affected patients (AAV2-REP1).…”

Quantification of RPE Changes in Choroideremia Using a Photoshop-Based Method

“…Several trials of AAV2-REP1 gene therapy have been published, and all of them used change in BCVA as their primary end points. 3 , 5 – 7 As all delivered the vector by subretinal injections and were designed to treat only the central retina, BCVA was a reasonable primary end point. However, some future gene therapy products in the pipeline aim to use an intravitreal approach to treat the whole retina (e.g., 4D-110; 4D Molecular Therapeutics, CA).…”

“…In previously reported trials of CHM gene therapy, ETDRS (Early Treatment Diabetic Retinopathy Study) letter acuity was used as a primary end point. [3][4][5][6][7] As many CHM patients retain 20/20 visual acuity before age 40 years, 8 using visual acuity as the primary outcome measurement would not fully reflect the efficacy of an intravitreal gene therapy targeting the whole retina. For that reason, we are interested in exploring outcome measures beyond visual acuity in CHM.…”

Is Viral Vector Gene Delivery More Effective Using Biomaterials?

“…Most clinical trials to date have employed viral vectors for the delivery of genetic material. [76][77][78] Generally, viral vectors are considered to be capable of efficiently transfecting cells, and can achieve long-term expression of desired genes for sustained therapeutic effects. For these reasons, we will limit the scope of this review to gene therapy using viral vectors.…”