Adenoviral Vector-Delivered Pigment Epithelium-Derived Factor for Neovascular Age-Related Macular Degeneration: Results of a Phase I Clinical Trial

Abstract

Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 10(6) to 10(9.5) particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were negative. At 3 and 6 months after injection, 55 and 50%, respectively, of patients treated with 10(6)-10(7.5) PU and 94 and 71% of patients treated with 10(8)-10(9.5) PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 months was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 10(8) PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Engineering of PEDF-Expressing Primary Pigment Epithelial Cells by the SB Transposon System Delivered by pFAR4 Plasmids

“…To meet such treatment modality, in 2006, Campochiaro and colleagues delivered the gene encoding PEDF to the retina of nvAMD patients using adenoviral (Ad) delivery and reported significant improvement in 25% of patients after 12 weeks and no harmful side effects 7, 8. However, no follow-up to the trial has been reported.…”

“…Currently, three additional gene therapy clinical trials are ongoing (https://clinicaltrials.gov/): trial NCT01494805 is based on the use of an adeno-associated viral (AAV) vector encoding sFlt-1, a splice variant of VEGF receptor 1; trials NCT01301443 and NCT01678872 are based on the use of a lentiviral vector expressing endostatin and angiostatin (RetinoStat). Aside from the results reported by Campochiaro et al., 8 the only other available data are from two Association for Research in Vision and Ophthalmology abstracts in 2014 and 2016 (M. Davies et al., 2014, Invest. Ophthalmol.…”

Progress and Prospects: Gene Therapy Clinical Trials (Part 1)

“…A phase I study has been conducted to evaluate the safety and tolerability of a single intravitreal injection of an adenoviral vector expressing the anti-angiogenic cytokine pigment epithelium-derived factor (PEDF). 2 In this multicentre dose-escalation trial that involved 28 patients, a single intravitreal injection of adenoviral vector (E1-, partial E3-, E4-deleted) was generally well tolerated. Signs of mild-to-moderate transient intraocular inflammation were reported in 25% of patients but no dose-limiting toxicities or serious adverse events attributed to the study drug were identified.…”

AAV-mediated gene therapy for retinal disorders: from mouse to man

“…The results of experimental studies have led to the development of a phase I clinical trial of adenovirus-mediated PEDF expression by intravitreal vector delivery in individuals with neovascular AMD. 97 Patients in this trial developed treatable inflammatory responses following vector administration, and only the group of patients receiving the highest dose of virus showed some improvements in outcome measures, such as neovascular lesion size. 97 To maximize the treatment potential of PEDF, a vector, such as AAV, that does not elicit immune responses would be better suited to delivering long-term, stable treatment effects.…”