I-Corps: Translation Potential of an orally administered, non-toxic family of weight loss drugs for treating obesity and related diseases

This I-Corps project is based on the development of a treatment for obesity and related diseases that works by increasing energy expenditure. Currently, GLP-1 weight loss drugs, which work by controlling appetite, are the most effective commercially available treatment for obesity. However, preference for oral medications or an inability to tolerate the side effects are two reasons why patients desist from taking GLP-1. This technology is an orally administered treatment that targets energy expenditure to promote weight loss. These drugs increase energy expenditure and decrease fat mass without affecting appetite or muscle mass, an ideal solution for older patients who need to preserve muscle mass while losing weight. It may serve as a standalone therapy or combination therapies alongside GLP-1 drugs for treating obesity and related diseases, such as liver steatosis, or diabetes. This I-Corps project utilizes experiential learning coupled with first-hand investigation of the industry ecosystem to assess the translation potential of an oral therapeutic for obesity and related diseases based on choline kinase alpha (ChoKα) inhibitors. These inhibitors increase energy expenditure rather than controlling appetite. Cell models demonstrated that ChoKα inhibitors prevent adipogenesis and increase thermogenesis via the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. ChoKα inhibitors can prevent weight gain in a mouse model under a high fat diet, cause weight loss, as well as improve liver fat profiles and glucose tolerance. ChoKα inhibitors have been demonstrated to have favorable toxicity profiles in cell mouse models making these favorable candidates for the development of a non-toxic weight-loss treatment. Moreover, ChoKα inhibitors are synergistic with the GLP-1 agonist semaglutide, suggesting that ChoKα inhibitors could be developed as effective therapies in combination with existing medications. This technology may serve as an alternative standalone therapy, as part of combination therapies, and as replacement therapies for treating obesity and related diseases. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.