Complement Factor H-based Therapeutic Strategies in Macular Degeneration

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DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic ab- normalities and environmental insults. AMD is the leading cause of blindness for Americans over age sixty. As the population ages, the prevalence of AMD will continue to grow, reaching a maximum risk rate of ~30% at age 75. Since smoking significantly increases the risk of AMD and there is a 20% higher incidence of smoking in veterans than in the general U.S. adult civilian population, the VA system will have to provide care for poten- tially up to 7 millio or more AMD cases. Current available treatments focus on the late stage of the disease (choroidal neovascularization; CNV); however, those come with significant risks and only target subpopulations of AMD patients. No treatment is available for early AMD (>85% of all cases). Thus it is paramount that we learn on how to detect AMD early and develop treatments that allow for early disease prevention. While mech- anistic studies have shown that inflammation and smoking are fundamental components of both forms of AMD, genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing AMD. One of the most detrimental mutations occurs in factor H (fH) an essential inhibitor in the alternative pathway (AP) of the complement cascade. Overall, it has been hypothesized that inadequate con- trol of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. A recent clini- cal trial (Genentech; lampalizumab blocking an activator of the AP), supports the hypothesis that the AP is a critical target in AMD. We have established that complement, and in particular AP activity is involved in differ- ent mouse models of AMD, including smoke-induced ocular pathology and laser-induced CNV. Finally, we have generated a targetable CFH, CR2-fH. CR2-fH uses the Complement Receptor 2 domain to specifically target factor H to sites of complement activation. The CR2 domain ensures targeting to membranes without relying on the endogenous ligand-binding domains present in CFH that harbor some of the genetic mutations. We have demonstrated efficacy in vitro and in vivo for reducing AP-dependent pathology using CR2-fH. One of the limitations of protein-based therapeutics is delivery. For short-term treatments, intravitreal injections are used for long-term treatments, other avenues need to be explored. Here we wish to test two therapeutic strat- egies in models of AMD: delivery of CR2-fH using AAV vector therapy using both preventative and therapeutic applications. Here we will be guided by our overall hypothesis that pathologic activation of the AP of comple- ment injures the RPE, and ultimately leads to the development of AMD. We further hypothesize that long-term delivery of the alternative pathway inhibitor CFH will provide an effective therapy for AMD.