Therapies that target Vascular Endothelial Growth Factor (VEGF) represent a recent, significant advance in the treatment of exudative age-related macular degeneration (AMD). However, VEGF inhibition appears to exert its beneficial effect mostly via an anti-permeability action resulting in resolution of intra and subretinal edema, as the actual CNV lesion does not markedly involute. Visual loss however, occurs not only from hemorrhaging but from inflammation and the growth of scar tissue leading to tractional retinal detachment. These other aspects of the pathology are not addressed by current anti-VEGF treatments. Targeting additional elements of the angiogenic and extravascular cascade associated with AMD could provide a more effective and synergistic means of therapy. Growing evidence suggests that the bioactive lipid sphingosine 1-phosphate (S1P) could contribute to both the early and late stages of maladaptive retinal remodeling associated with exudative AMD. S1P has a pronounced non-VEGF dependent proangiogenic effect. S1P also stimulates migration, proliferation and survival of multiple cell types, including fibroblasts, pericytes, endothelial and inflammatory cells-the same cells that participate in the multiple maladaptive processes of exudative AMD. S1P is linked to the production and activation of VEGF, FGF, PDGF and other growth factors (GFs) implicated in the pathogenesis of exudative AMD. Finally, S1P may modulate the maturation of na?ve vasculature, a process leading to a loss of sensitivity to anti-angiogenic agents. Inhibiting the action of S1P could be an effective therapeutic treatment for exudative AMD that may offer significant advantages over exclusively anti-VEGF approaches or act synergistically with them to address the complex processes that ultimately lead to visual loss. Lpath has recently developed Sphingomab, a novel murine monoclonal antibody directed against S1P. Sphingomab acts as a molecular sponge to selectively absorb S1P from the extra cellular fluid, lowering the effective concentration of S1P. We believe that Sphingomab can inhibit both the vascular and extravascular components of AMD. In a murine model of laser induced CNV, a modest dose of Sphingomab markedly reduced the volume of CNV that formed. In other models, Sphingomab has demonstrated efficacy in 1) Slowing inflammatory responses; 2) Inhibiting neovascularization; and 3) Reducing scar formation. The goal of this proposal is to investigate the efficacy of Sphingomab to reduce the multiple processes of CNV associated with AMD. Using the rodent model of CNV, Sphingomab's effects on inflammation, CNV, blood vessel maturation, edema and scar formation will be evaluated. In addition, the pharmacokinetic and safety profiles of Sphingomab, administered into the eye, will be determined. Finally, the optimal therapeutic dosing regimen, in mice, will be established. The successful completion of these specific aims will demonstrate Sphingomab's unique potential to affect the multiple underlying pathologies of CNV and demonstrate its value as a therapeutic that is distinct, and perhaps complementary, to anti-VEGF treatments. ? ? ? ?
