Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic abnormalities 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. Current available treatments focus on the late stage of the disease (choroidal neovascular- ization;CNV);however, those come with significant risks and only target subpopulations of AMD patients. No treatment is available for early or dry 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 mechanistic 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 (CFH) an essential inhibitor in the alternative pathway (AP) of the complement cascade. Overall, it has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. Of interest, a recent phase II clinical trial reported significant protection against the progression of geographic atrophy in subgroups of patients, using a monoclonal antibody against complement factor D (lampalizumab), a required activator of the AP. We have established that complement, and in particular AP activity is involved in different mouse models of AMD, including smoke-induced ocular pathology, laser-induced CNV and loss of superoxide activity. 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, and have demonstrated efficacy in vitro and in vivo for reducing AP-dependent pathology. 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 strategies in models of AMD: 1) delivery of CR2-fH using AAV vector therapy;and 2) production and delivery of CR2-fH by encapsulated cell technology. Here we will be guided by our overall hypothesis that pathologic activation of the AP of complement injures the RPE, and ultimately leads to the development of AMD. We further hypothesize that long-term delivery of the AP inhibitor CR2-fH will provide an effective therapy for AMD.

Public Health Relevance

Risk factors for age-related macular degeneration (AMD) involve single nucleotide polymorphisms in the alternative pathway (AP) of complement inhibitor factor H, as well as oxidative stress. We have developed and validated a targeted AP inhibitor as a possible therapeutic agent (CR2-fH) for the treatment of AMD. Here we wish to test two long-term therapeutic strategies in models of AMD: 1) delivery of CR2-fH using AAV vector therapy;and 2) production and delivery of CR2-fH by encapsulated cell technology.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Shen, Grace L
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Medical University of South Carolina
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United States
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