Multivalent Conjugates of Sonic Hedgehog to Accelerate Diabetic Wound Healing

Valitor, Inc., Berkeley CA

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Abstract

DESCRIPTION: In 2012, nearly one million Americans with diabetes were diagnosed with a lower extremity ulcer, and failure of these wounds to heal resulted in more than 75,000 lower extremity amputations. Valitor, Inc. is developing protein-polymer therapeutics to overcome the micro vascular consequences of diabetic wound healing. We designed our therapy to complement the standard practice of diabetic ulcer management and to reduce the costly serial effort required for debridement and clinical observation of these slowly healing wounds. Our patented technology is a bio conjugation process that enables us tether Sonic hedgehog (Shh), an important angiogenic factor, to linear chains of hyaluronic acid (HyA) at defined Shh:HyA ratios (i.e., valency). In Phase I of this project, we verified that Shh valency correlated with enhanced Shh-induced cellular functions, including downstream angiogenic signaling, which were substantially unregulated relative to equimolar concentrations of unconjugated Shh. We further demonstrated that after treatment with multivalent Shh conjugates (mvShh), full- thickness excisional wounds in db/db diabetic mice exhibited significantly greater neovascular density and faster closure times compared to wounds treated with unconjugated Shh or vehicle controls. Our overall goal during Phase II is to build on these promising proof-of-mechanism results by completing the lead optimization process and to advance mvShh to as a candidate for pre-clinical studies.