Abstract
Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD.
Highlights
Age related macular degeneration (AMD) is the leading cause of central vision loss and blindness amongst the elderly in the developed world
Media from cells infected with AdCAGsCD59 confirmed the expression and secretion of soluble forms of CD59 (sCD59) (Figure 1B), a protein consisting of a number of N-glycosylated forms of approximately 14–18 kDa
No sCD59 was detected in the lysate or media from AdCAGGFP-infected ARPE-19 cells
Summary
Age related macular degeneration (AMD) is the leading cause of central vision loss and blindness amongst the elderly in the developed world. The remaining 90% of patients suffer from the nonexudative or dry form of AMD characterized by the deposition of drusen or lipoproteinaceous deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane. A subset of advanced AMD patients suffer from geographic atrophy (GA), characterized by a loss of RPE cells and subsequent retinal degeneration (reviewed in [1]). Wet AMD is the major contributor to vision loss and this form of AMD can be treated effectively with FDA-approved vascular endothelial growth factor antibody ranibizumab [2]. This current standard of care does not block the progression of dry AMD. There is currently no effective treatment available for 90% of AMD patients
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