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.

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 for the treatment of AMD. Here we wish to test an AAV5-vector-based delivery for CR2-fH in models of dry and wet AMD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01RX000444-05A1
Application #
8782008
Study Section
Sensory Systems/Communication (RRD3)
Project Start
2010-10-01
Project End
2018-09-30
Budget Start
2014-10-01
Budget End
2015-09-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
039807318
City
Charleston
State
SC
Country
United States
Zip Code
29401
Schnabolk, Gloriane; Beon, Mee Keong; Tomlinson, Stephen et al. (2017) New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement. J Ocul Pharmacol Ther 33:400-411
Obert, Elisabeth; Strauss, Randy; Brandon, Carlene et al. (2017) Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, ?CT1, reduces VEGF-dependent RPE pathophysiology. J Mol Med (Berl) 95:535-552
Bowers, Jacob S; Nelson, Michelle H; Majchrzak, Kinga et al. (2017) Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion. JCI Insight 2:e90772
Shi, Yi; Obert, Elisabeth; Rahman, Bushra et al. (2017) The Retinol Binding Protein Receptor 2 (Rbpr2) is required for Photoreceptor Outer Segment Morphogenesis and Visual Function in Zebrafish. Sci Rep 7:16207
Busch, Catharina; Annamalai, Balasubramaniam; Abdusalamova, Khava et al. (2017) Anaphylatoxins Activate Ca2+, Akt/PI3-Kinase, and FOXO1/FoxP3 in the Retinal Pigment Epithelium. Front Immunol 8:703
Ishii, Masaaki; Rohrer, Bärbel (2017) Bystander effects elicited by single-cell photo-oxidative blue-light stimulation in retinal pigment epithelium cell networks. Cell Death Discov 3:16071
Lobo, Glenn P; Fulmer, Diana; Guo, Lilong et al. (2017) The exocyst is required for photoreceptor ciliogenesis and retinal development. J Biol Chem 292:14814-14826
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Holers, V Michael; Tomlinson, Stephen; Kulik, Liudmila et al. (2016) New therapeutic and diagnostic opportunities for injured tissue-specific targeting of complement inhibitors and imaging modalities. Semin Immunol 28:260-7
Smith, Amena W; Rohrer, Baerbel; Wheless, Lee et al. (2016) Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis. J Neurochem 139:270-284

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