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Hum Genet. 2016 Mar;135(3):327-43. doi: 10.1007/s00439-016-1637-y. Epub 2016 Jan 29.

Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial.

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Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA.
Department of Ophthalmology, College of Medicine, Al-Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.
Department of Ophthalmology, Institute for Genomic Medicine, University of California San Diego, San Diego, CA, USA.
Chengdu JiaChuan Biomedicine Co., Ltd, Chengdu, China.
Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou, China.
Department of Ophthalmology, University of Florida, Gainesville, USA.
Department of Medicine, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
Rose-Silverthorne Retinal Degenerations Laboratory, Retina Foundation of the Southwest, Dallas, USA.
Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Beckman Vision Center, University of California San Francisco, San Francisco, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, USA.
Veterans Administration Healthcare System, San Diego, CA, 92093, USA.
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.


MERTK is an essential component of the signaling network that controls phagocytosis in retinal pigment epithelium (RPE), the loss of which results in photoreceptor degeneration. Previous proof-of-concept studies have demonstrated the efficacy of gene therapy using human MERTK (hMERTK) packaged into adeno-associated virus (AAV2) in treating RCS rats and mice with MERTK deficiency. The purpose of this study was to assess the safety of gene transfer via subretinal administration of rAAV2-VMD2-hMERTK in subjects with MERTK-associated retinitis pigmentosa (RP). After a preclinical phase confirming the safety of the study vector in monkeys, six patients (aged 14 to 54, mean 33.3 years) with MERTK-related RP and baseline visual acuity (VA) ranging from 20/50 to <20/6400 were entered in a phase I open-label, dose-escalation trial. One eye of each patient (the worse-seeing eye in five subjects) received a submacular injection of the viral vector, first at a dose of 150 µl (5.96 × 10(10)vg; 2 patients) and then 450 µl (17.88 × 10(10)vg; 4 patients). Patients were followed daily for 10 days at 30, 60, 90, 180, 270, 365, 540, and 730 days post-injection. Collected data included (1) full ophthalmologic examination including best-corrected VA, intraocular pressure, color fundus photographs, macular spectral domain optical coherence tomography and full-field stimulus threshold test (FST) in both the study and fellow eyes; (2) systemic safety data including CBC, liver and kidney function tests, coagulation profiles, urine analysis, AAV antibody titers, peripheral blood PCR and ASR measurement; and (3) listing of ophthalmological or systemic adverse effects. All patients completed the 2-year follow-up. Subretinal injection of rAAV2-VMD2-hMERTK was associated with acceptable ocular and systemic safety profiles based on 2-year follow-up. None of the patients developed complications that could be attributed to the gene vector with certainty. Postoperatively, one patient developed filamentary keratitis, and two patients developed progressive cataract. Of these two patients, one also developed transient subfoveal fluid after the injection as well as monocular oscillopsia. Two patients developed a rise in AAV antibodies, but neither patient was positive for rAAV vector genomes via PCR. Three patients also displayed measurable improved visual acuity in the treated eye following surgery, although the improvement was lost by 2 years in two of these patients. Gene therapy for MERTK-related RP using careful subretinal injection of rAAV2-VMD2-hMERTK is not associated with major side effects and may result in clinical improvement in a subset of patients.

[Indexed for MEDLINE]

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