Neovascular AMD

A Phase 1 dose escalation study investigating subretinal administration of RetinoStat (Oxford BioMedica) met its primary endpoints, as the results demonstrated that the novel recombinant gene-based therapy was safe and well-tolerated in patients with advanced neovascular age-related macular (AMD), reported Andreas K Lauer MD, at WOC2016 in Guadalajara, Mexico. Recently this work has been published in Human Gene Therapy.¹ Although there was no substantive change in BCVA during follow-up to 48 weeks, functional improvement was not expected as the enrolled eyes already had central subretinal fibrosis from their disease. However, assays of aqueous humour obtained through anterior chamber taps showed significant and persistent increased expression of the endostatin and angiostatin genes delivered with a proprietary equine infectious anaemia virus-based lentiviral vector (LentiVector). 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 · 105 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy said Dr Lauer, Casey Eye Institute, Oregon Health & Science University, Portland, United States. “Although we presently have numerous treatment options that are effective in halting or delaying vision loss in eyes with neovascular AMD, there is a tremendous need to try to reduce the treatment burden. Anti-angiogenic gene therapy with RetinoStat aimed to address this need for its potential for longer duration of effect than current therapies and can produce localized steady-state levels of therapeutic proteins at the retina,” he said. “Further development of RetinoStat for the treatment of exudative AMD and other indications are being explored. There is still much to be learned.” The Phase 1 study enrolled 21 eyes of 21 patients and evaluated three doses of RetinoStat. Three eyes each were treated with the lowest and medium doses, and a total of 15 eyes received the highest dose. The treatment was performed in the operating room and involved pars plana vitrectomy and a single injection into a subretinal bleb. With the exception of one eye that developed a macular hole after vitrectomy, the bleb was created superotemporally or temporally because the central retina was tethered by scarring. A total of 247 adverse events were reported, but they were mostly non-ocular and judged unrelated to the treatment. Twenty mild and three moderate adverse events were reported as related to the surgical procedure. Biodistribution and immune analyses found no evidence of systemic delivery of the lentiviral vector or changes in VEGF expression following subretinal administration of RetinoStat. Patients did not receive any immunosuppression, and no immune responses were mounted toward the lentiviral vector. Intraocular inflammation was observed only at the highest dose of RetinoStat evaluated and only in some eyes, but it was transient and controlled with topical prednisolone acetate. Some study participants are being followed for 15 years. Reference: Campochiaro PA, Lauer AK, Sohn EH, Mir TA, Naylor S, Anderton MC, Kelleher M, Harrop R, Ellis S, Mitrophanous KA. Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study. Hum Gene Ther. 2017 Jan;28(1):99-111. doi: 10.1089/hum.2016.117. PubMed PMID: 27710144; PubMed Central PMCID: PMC5278797. www.dropbox.com/s/i87ybbcv8p7667y/2013%20AKL%20Retinostat%20copy.mov?dl=0 Andreas K. Lauer, MD  lauera@ohsu.edu