title: The complement regulatory protein CD59: insights into attenuation of choroidal neovascularization.
abstract: Complement activation is associated with age-related macular degeneration (AMD), with the retinal pigment epithelium (RPE) being one of the main target tissues. In AMD, disease severity is correlated with the formation of the membrane attack complex (MAC), the terminal step in the complement cascade, as well as diminished RPE expression of CD59, a membrane-bound regulatory protein of MAC formation. This has prompted the search for therapeutic strategies based on MAC inhibition, and soluble forms of CD59 (sCD59) have been investigated in mouse laser-induced choroidal neovascularization, a model for "wet" AMD. Unlike membrane-bound CD59, sCD59 provides relatively poor cell protection from complement, and different strategies to increase sCD59 activity at the cell membrane level have been investigated. These include increasing the circulatory half-life of sCD59 by the addition of an Fc moiety; increasing the half-life of sCD59 in target tissues by modifying CD59 with a (non-specific) membrane-targeting domain; and by locally overexpressing sCD59 via adenoviral vectors. Finally, a different strategy currently under investigation employs complement receptor (CR)2-mediated targeting of CD59 exclusively to membranes under complement attack. CR2 recognizes long-lasting membrane-bound breakdown activation fragments of complement C3. CR2-CD59 may have greater therapeutic potential than other complement inhibitory approaches, since it can be administered either systemically or locally, it will bind specifically to membranes containing activated complement activation fragments, and dosing can be regulated. Hence, this strategy might offer opportunities for site-specific inhibition of complement in diseases with restricted sites of inflammation such as AMD.
authors.affiliation: Ralph H. Johnson VA Medical Center, Division of Research, 29401, Charleston, SC, USA, faith@musc.edu.
authors.forename: Gloriane
authors.initials: G
authors.lastname: Schnabolk
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Bärbel
authors.initials: B
authors.lastname: Rohrer
mesh_terms: D000818:Animals; D018957:CD59 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020256:Choroidal Neovascularization / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D015938:Complement Membrane Attack Complex / Q000276:immunology / Q000378:metabolism*; D003165:Complement System Proteins / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D008268:Macular Degeneration / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D051379:Mice
chemical_list: D018957:CD59 Antigens; C539311:CD59a protein, mouse; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins