Topical squalamine offers novel, promising therapy for nAMD
By Cheryl Guttman Krader
Topical squalamine (Ohr Pharmaceutical), a small molecule being investigated for the treatment of neovascular age-related macular degeneration (nAMD) and other retinal vascular diseases, represents a novel therapy because of its mode of administration and multimodal mechanism of anti-angiogenic activity.
Glenn L. Stoller, MD, chief scientific officer, Ohr Pharmaceutical, New York, outlined the mechanism of action of squalamine. He explained that it is a calmodulin-binding molecule that acts within vascular endothelial cells.
The molecule enters the cells through cell membrane invaginations known as caveolae. Inside the cell, squalamine sequesters calmodulin away from its receptors and causes global suppression of calmodulin-dependent signaling that results in inhibition of VEGF- and basic fibroblast growth factor (bFGF)-mediated cell signaling, as well as decreased expression of cell surface integrins.
Different mode of action
Dr. Stoller differentiated squalamine’s anti-VEGF mode of action from that of existing anti-VEGF therapies.
“The clinically available anti-VEGF agents used to treat retinal diseases are VEGF ligand binding agents that prevent VEGF from binding to its receptor, but they cannot prevent cell signaling induced by VEGF that is able to bind to the VEGF receptor,” Dr. Stoller said. “With its different mechanism of action, squalamine can block all of the downstream effects that occur after VEGF binds to its receptor.”
Blockade of bFGF is also an important component of squalamine’s activity because bFGF is a potent mitogen for vascular endothelial cells and for fibroblasts that mediate the fibrosis that can occur with wet AMD, he added. The significance of decreasing integrin expression is that integrins are overexpressed on endothelial cells during angiogenesis and facilitate the growth and survival of the newly forming vessels.
Dr. Stoller explained that because it is an amphiphilic molecule, topically applied squalamine is able to penetrate to the posterior segment through a transscleral route and reach therapeutic concentrations in the choroid where it has a prolonged intracellular half-life.
“Squalamine happens to be particularly ‘sticky’ to the choroid because of its cationic side chain,” Dr. Stoller said….
Source: Modern Retina