Development of a one-time gene therapy for age-related macular degeneration targeting CD146

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Neovascular age-related macular degeneration (wet AMD) is a multifactorial disease leading to loss of central vision. It is the leading cause for blindness in the elderly western population and poses a significant clinical and economic burden. Implementation of anti-VEGF drugs like aflibercept, bevacizumab, ranibizumab and more recently brolucizumab in clinical practice has dramatically improved the prognosis of wet AMD. However, currently there is no cure for wet AMD and available treatments cannot prevent the development of atrophy and scar formation. Thus, it is mandatory to find new treatment options to address the unmet medical need in this devastating sight threatening disease. Here, we propose the development of a one-time gene therapy treatment of AMD based on a novel therapeutic target (CD146; gene name: MCAM). Different from previous approaches that directly inhibit the growth factor VEGFA, our approach targets both the proangiogenic and proinflammatory cell adhesion molecule CD146 to inhibit multiple signaling pathways crucially involved in the pathogenesis of AMD-related vision loss. Own preliminary results suggest that inhibition of CD146 reduces the formation of leaky choroidal blood vessels and the extent of lesion formation in the laser-induced choroidal neovascularization (CNV) mouse model of wet AMD. Previously, we generated variants of recombinant antibody fragments (Fabs) directed against mouse and human CD146 and confirmed high affinity binding to the extracellular domain of human CD146. In this project, we will further characterize the recombinant anti-CD146 Fabs and test dem for efficacy in relevant in vitro models and in the CNV mouse model of wet AMD. The most promising variants will then be produced as AAV-vectorized versions and tested again for in vitro and in vivo efficacy. In an alternative approach, we will generate and test AAV vectors expressing CRISPR-Cas9 and sgRNAs targeting the mouse Mcam gene for inactivation. Our overarching goal is to provide preclinical proof of concept for a novel, one-time gene therapy approach against wet AMD and to select an optimal candidate for future clinical translation.