Optimization and Pre-Clinical Studies of a Protein Therapeutic for Recruiting Brown Adipocytes

Obesity has reached epidemic proportions in the US and plays a major role in the development of typediabetes and cardiovascular diseaseThere remains a very significant need for better treatmentsWhile current weight loss agents act by suppressing appetitestrategies that can safely enhance energy expenditure have the potential to effectively treat obesityBrown adipose tissueBATis a thermogenic tissue that uniquely expresses mitochondrial UnCoupling ProteinUCPThis protein dissipatesin a regulated fashionthe electrochemical gradient in the mitochondria of brown adipocytes as heatand thus plays an important role in the maintenance of body temperature and energy balanceBAT is a flexible tissue that normally enlarges or atrophies over time depending on environmental temperatureIn numerous animal modelsenhancement of BAT mass has been shown to cause weight loss and diabetes resistanceWhile BAT was until recently thought to be insignificant in adult humansdata obtained in the past several years with PET imaging show that adults in fact have significant amounts of functional BATand that the amount of BAT in individuals is strongly correlated with leannessFurthermorethe genetic locus most tightly linked with human obesityFTOwas recently shown to cause defective recruitment of new brown adipocytesUntil recently no brown adipocyte stem cell had been identifiedWe discovered human skeletal muscleresident brown adipocyte progenitor cells that under appropriate conditions become fully functional brown adipocytesexpressing high levels of UCPand having a very high metabolic rateUsing these progenitors we identified a protein factor that is secreted by brown adipocytes and in turn promotes the recruitment of additional brown adipocytes in cultureA slightly truncated version of this protein with a somewhat longer circulating half lifewhich is already marketed for an unrelated acute indicationwas tested in Diet Induced ObeseDIOmicea highly predictive animal model for human obesity and insulin resistanceMarked decreases in body weight and body fatas well as improvements in glucose metabolism were observed in aday studyHoweverthe still relatively short plasma half life of the tested agent requires that it be injected at least every other daya major challenge for a chronic metabolic disease indicationIn the proposed workwe therefore aim to generate protein analogs with significantly extended plasma halflife that show similar or better efficacy in DIO miceSuch a compound could be administered once weekly or less frequentlyWe will evaluate protein yieldmanufacturabilityconfirm the activity of the analogs in vitroand determine their plasma half life in miceThose compounds with the best profile will be tested for efficacy in DIO miceIf this work is successfulwe plan to rapidly move to select a lead and backup compound and initiate IND enabling studies with a novelbrown fat recruiting product candidate for the treatment of obesity and diabetes