Engineered Biotherapeutic Agent for Treatment of Post-Traumatic Osteoarthritis

PROJECT SUMMARY/ABSTRACT Post-traumatic osteoarthritis (PTOA) is a degenerative disease of cartilage brought on by traumatic injury to the articular joints. Acute joint injury is followed by severe joint pain and inflammation. This results in much more rapid degeneration of cartilage than in other forms of osteoarthritis, due to the joint instability caused by trauma as well as the increase in proinflammatory cytokines that accelerate degeneration. PTOA affects 5.6 million Americans, with an estimated $11.79 billion associated with direct treatment costs for its treatment. There are no approved treatments that stop or alter the progression of the disease, and complete degeneration of the articular cartilage can necessitate joint replacement surgery. This may require surgical revision in approximately 10 years, a particularly undesirable outcome in younger patients with longer life expectancies. ProViZiGen has developed a novel protein-engineered injectable therapeutic hydrogel system, HydroGEN that forms a gel when injected into the joint space and provides sustained delivery of an anti-inflammatory and chondroprotective therapeutic molecule. Our recent preclinical investigation in a rabbit anterior cruciate ligament (ACL) transection model has shown that immediate delivery of HydroGEN significantly prevents the development of PTOA after joint injury and delivery 8 weeks after the point of injury has therapeutic effects promoting endogenous cartilage repair. In this Phase I STTR, we aim to determine stability and lack of toxicity of HydroGEN to establish functional gelation and establish safe dosing. In Aim I, we will determine the stability and mechanics of HydroGEN by assessing the protein’s microstructure and macrostructure, as well as its rheologic properties as a function of temperature and time to determine its functionality as an in situ gelling injectable therapeutic. In Aim II, we will establish the lack of toxicity and selective biodistribution of HydroGEN in a rat model of intraarticular injection. Successful completion of these aims will prepare ProViZiGen for filing a BLA with the FDA, with large animal PTOA model investigation (Phase II) leading to first in human trials.