title: Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial.
abstract: 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.
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.|Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Ghazi
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Emad B
authors.initials: EB
authors.lastname: Abboud
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Sawsan R
authors.initials: SR
authors.lastname: Nowilaty
authors.affiliation: Department of Ophthalmology, College of Medicine, Al-Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkuraya
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alhommadi
authors.affiliation: 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.
authors.forename: Huimin
authors.initials: H
authors.lastname: Cai
authors.affiliation: Chengdu JiaChuan Biomedicine Co., Ltd, Chengdu, China.|Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Hou
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, USA.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Deng
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, USA.
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.affiliation: Department of Medicine, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Almaghamsi
authors.affiliation: Department of Medicine, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Fahad
authors.initials: F
authors.lastname: Al Saikhan
authors.affiliation: Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Hassan
authors.initials: H
authors.lastname: Al-Dhibi
authors.affiliation: Rose-Silverthorne Retinal Degenerations Laboratory, Retina Foundation of the Southwest, Dallas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Birch
authors.affiliation: Department of Ophthalmology, Institute for Genomic Medicine, University of California San Diego, San Diego, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.affiliation: Beckman Vision Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: LaVail
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Vollrath
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Erger
authors.affiliation: Chengdu JiaChuan Biomedicine Co., Ltd, Chengdu, China.|Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou, China.
authors.forename: Wenqiu
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Conlon
authors.affiliation: Department of Ophthalmology, Institute for Genomic Medicine, University of California San Diego, San Diego, CA, USA.|Veterans Administration Healthcare System, San Diego, CA, 92093, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hauswirth
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.identifier: http://orcid.org/0000-0003-4158-341X
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D023381:Endpoint Determination; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008251:Macaca; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011183:Postoperative Complications / Q000628:therapy; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000628:therapy*; D058471:Subretinal Fluid; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity; D055815:Young Adult; D000076202:c-Mer Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase
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