Charlesson, LLC — Department of Health and Human Services SBIR Phase I: W

Description

DESCRIPTION provided by applicant Age related macular degeneration AMD is a common disease of the central retina and remains a leading cause of vision loss and blindness in elderly Americans Currently the standard of care for wet AMD is intravitreal vascular endothelial growth factor VEGF inhibitors However these therapies are not always effective in all patients AMD is a multi factorial disease involving numerous pathogenic factors that contribute to the pathogenesis of AMD Thus targeting a VEGF or VEGF receptors alone cannot benefit all cases of AMD and there is a great demand for developing more effective therapeutic options with multiple targets or new targets Accumulated evidence has demonstrated that the over activation of Wnt pathway plays an important role in AMD The Wnt pathway is involved in multiple pathological processes of AMD including the formation of new blood vessels vascular leakage inflammation fibrosis and oxidative stress as it regulates many Wnt target genes which are known pathogenic factors e g VEGF platelet derived growth factor PDGF intercellular adhesion molecule ICAM tumor necrosis factor alpha TNF a cyclooxygenase Cox connective tissue growth factor CTGF and fibronectin FN Since Wnt inhibitors can simultaneously down regulate multiple pathogenic factors they should be more superior to anti VEGF therapeutics Low density lipoprotein receptor related protein LRP a cell surface receptor is an essential component for the activation of the Wnt pathway Thus LRP becomes an attractive molecular target for treating AMD Through generating and screening a series of mouse anti human LRP monoclonal antibodies mAbs F mab has been identified as a specific mAb against human LRP and a potent Wnt inhibitor Preliminary data showed that F mab specifically recognizes the ligand binding domain of LRP blocks the over activation of Wnt pathway down regulates the over expression of WNT target genes including VEGF TNF a ICAM and CTGF and alleviates multiple pathological processes of AMD such as retinal vascular leakage inflammation and neovascularization NV As AMD is characterized by multiple pathological processes the inhibitory effects of F mab on multiple pathogenic factors make it a promising drug candidate for the treatment of AMD The therapeutic potential of F mab strongly warrants further development of an antibody based therapy modality which is suitable to clinical use in AMD patients Using complementarity determining region CDR grafting phage display techniques and antibody expression system we have produced a series of humanized antibodies Among them clone CLT showed high affinity to human LRP and potent inhibitory effect on the Wnt pathway corneal neovascularization and information These findings indicate that CLT is a promising drug candidate for AMD This SBIR Phase I project will serve as a proof of concept study to evaluate the in vivo efficacies of CLT on Wnt signaling activation Wnt target gene expression and chroidal neovascularization CNV in a rat model of laser induced CNV The program includes two specific aims Aim will determine the effects of CLT on the Wnt pathway activation and Wnt target gene expression Aim will evaluate the efficacies of CLT on CNV The proposed studies will lay a solid groundwork for future preclinical studies of CLT in Phase II The project has potential to develop a therapy with a novel target other than VEGF to treat AMD This new therapeutic antibody could be applied together with anti VEGF agents or as an alternative PUBLIC HEALTH RELEVANCE Age related macular degeneration AMD remains a leading cause of vision loss and blindness in elderly Americans Current therapies have limited benefit and are not always effective in all patients with AMD Thus there is a great demand for developing more effective alternative options to improve the treatment of AMD The project will develop a treatment with a novel target other than VEGF to treat AMD