1. ¹Casey Eye Institute, Portland, OR
2. ²Cullen Eye Institute, Houston, TX
3. ³Jules Stein Eye Institute, Los Angeles, CA
4. ⁴University of Washington, Seattle, WA
5. ⁵GenVec, Gaithersburg, MD
6. ⁶Kresge Eye Institute, Detroit, MI
7. ⁷Wilmer Eye Institute, Baltimore, MD

Abstract

Neovascular age-related macular degeneration (AMD) is one of the leading causes of blindness, afflicting approximately 200,000 individuals/year in the United States. Pigment Epithelium-Derived Factor (PEDF), a naturally-occurring factor in the eye is a potent antiangiogenic factor. PEDF opposes not only VEGF but also other angiogenic stimuli such as FGF, PDGF and IL-8. In addition, PEDF is neuroprotective and thus may enhance preservation of retinal ganglion cells and photoreceptors that are essential for vision. To evaluate the safety and feasibility of intravitreal PEDF delivery via a second generation adenovector (AdPEDF) in patients with subfoveal CNV due to AMD, we conducted an open label, dose-escalation protocol with 8 dose levels (10⁶-10^9.5 pu in 1/2 log increments) in patients with active subfoveal CNV and best corrected visual acuity of 20/200 or worse in the study eye. After a single intravitreal injection of AdPEDF, 1 year follow-up consisted of periodic ocular exams, fluorescein angiograms, and laboratory evaluations including adenovirus neutralizing antibody titers and throat and urine cultures for adenovirus. Optical coherence tomography was performed as a substudy at 2 study sites. Six of 8 dose cohorts have been fully enrolled (n=18), and accrual is ongoing. Intravitreal AdPEDF has been well-tolerated and there have been no dose limiting toxicities or related severe adverse events. Three patients (two at 10^7.5 and one at 10^8.5 pu) had mild transient inflammation and Grade 1 elevation in intraocular pressure (IOP) thought to be probably or possibly related to the study drug. Neutralizing antibody titers did not increase at 3 months in 11 out of 12 patients and all adenoviral cultures were negative. Intravitreal injection of up to 10^8.5 pu of AdPEDF is well-tolerated and has not been associated with any serious short-term toxicity.