BLR&D Research Career Scientist Award Application

Ralph H Johnson Va Medical Center, Charleston SC

Investigators

Linked publications & trials

Abstract

Age-related macular degeneration (AMD) is a slowly progressing disease involving genetic abnormalities and environmental insults. It is the leading cause of blindness for older Americans; and as the population ages, the prevalence of AMD continues to grow. Treatments are available for choroidal neovascularization (CNV); but those come with risks and only target a subpopulation of AMD patients. No treatment is available for early AMD, whereas new treatments for geographic atrophy (GA; >85% of all cases), are limited in effi- cacy and come with significant side effects. This makes it paramount to develop diagnostic tools and a treatment for early disease intervention. My Two Merit awards study two aspects of AMD. The BX Award is focused on understanding how cell-cell communication is contributing to the spreading of disease through- out the posterior pole. Specifically, we ask how extracellular vesicles (EV), which are released from all cells in the body, contribute to distributing damage signal throughout the eye. Concomitantly, we are asking whether EV content could be used as biomarkers for disease. For the RX award, while mechanistic studies have shown that inflammation and smoking are fundamental components of AMD, genetic studies have demonstrated that polymorphisms in 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 complement alternative pathway (AP), suggesting that inadequate control of complement-driven inflammation is a major AMD risk factor. Following the many encouraging data in animal models and early phase clinical trials, approaches to block complement factor C3 (activator in the common terminal pathway, integrating all 3 pathways of com- plement activation, as well as complement factor C5 (activator in the terminal pathway) were recently FDA approved. However, both treatments are limited in efficacy and come with significant side effects. What these tow strategies have in common is that most of the drug is wasted on non-pathophysiologically im- portant target molecules; i.e., most complement components in fluids or tissue are not engaged in comple- ment activation and hence to reduce complement activation for example at the RPE, Bruch’s membrane (BrM) or choriocapillaris (CC), the majority of a given complement component has to be permanently inhib- ited to achieve the desired effect. In addition, complement components are made in the eye and systemical- ly, and many complement components can penetrate BrM; hence an almost unlimited reservoir of comple- ment proteins exists that needs to be controlled. Given these complications, we are building on our previous data. We are proposing to utilize antibodies and nanobodies against activated C3 to document complement activation in the eye as a diagnostic marker, as well as to document efficacy for target engagement for treatments. Second, by utilizing an “addressable” inhibitor that target to sites of complement activation re- gardless of the location (CR2-fH) delivered via gene therapy, we will follow up on our successful animal ex- periments by examining efficacy in 2D and 3D cell-based models of AMD, utilizing genetically characterized iPSC derived RPE and choroidal cells. Additional lab in the Rohrer lab not funded through VA is aiming to characterize disease mechanisms in AMD, focusing on deterioration of the outer blood retinal barrier (NEI- R01), as well as utilizing the CR2-fH strategy towards vision loss in traumatic brain injury (DoD EBrap Vi- sion Research Program). Overall, our work is designed to develop therapeutics and diagnostics in age- and injury-related vision loss towards clinical application, with the long-term goal of developing a treatment to improve veteran care and quality of life.