title: Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study.
abstract: Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat®). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 104(n = 3), 2.4 × 105(n = 3), or 8.0 × 105transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aqueous humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 weeks after injection of 2.4 × 105TU or 8.0 × 105TU at 57-81 ng/mL for endostatin and 15-27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent reduction in fluorescein angiographic leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 105TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.
authors.affiliation: 1 The Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.affiliation: 2 Casey Eye Institute, Oregon Health and Science University , Portland Oregon.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Lauer
authors.affiliation: 3 Department of Ophthalmology, University of Iowa Hospitals and Clinics , Iowa City, Iowa.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sohn
authors.affiliation: 1 The Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Tahreem A
authors.initials: TA
authors.lastname: Mir
authors.affiliation: 4 Formerly of Oxford BioMedica (UK) Ltd. , Oxford, United Kingdom .
authors.forename: Stuart
authors.initials: S
authors.lastname: Naylor
authors.affiliation: 5 Oxford BioMedica (UK) Ltd. , Windrush Court, Oxford, United Kingdom .
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Anderton
authors.affiliation: 5 Oxford BioMedica (UK) Ltd. , Windrush Court, Oxford, United Kingdom .
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelleher
authors.affiliation: 5 Oxford BioMedica (UK) Ltd. , Windrush Court, Oxford, United Kingdom .
authors.forename: Richard
authors.initials: R
authors.lastname: Harrop
authors.affiliation: 5 Oxford BioMedica (UK) Ltd. , Windrush Court, Oxford, United Kingdom .
authors.forename: Scott
authors.initials: S
authors.lastname: Ellis
authors.affiliation: 5 Oxford BioMedica (UK) Ltd. , Windrush Court, Oxford, United Kingdom .
authors.forename: Kyriacos A
authors.initials: KA
authors.lastname: Mitrophanous
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D043168:Angiostatins / Q000235:genetics; D015331:Cohort Studies; D043169:Endostatins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D056965:Injections, Intraocular; D016086:Lentivirus / Q000235:genetics*; D008268:Macular Degeneration / Q000235:genetics / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose
chemical_list: D043169:Endostatins; D043168:Angiostatins
keywords: age-related macular degeneration (AMD); equine infectious anemia viral (EIAV) vector; lentiviral vector; neovascularization; ocular gene therapy; subretinal injection