Development of a TAVI Device with a Reduced Crossing Profile

DESCRIPTION (provided by applicant): Obesity is considered the number one health problem in the US and Europe, affecting 10% to 30% of adult populations. Obese individuals are more likely to acquire a variety of secondary diseases including diabetes, heartproblems, immune deficiencies, some types of cancer, and osteoarthritis and they die younger than non-obese individuals. Obesity results from the development of too many fat cells (adipocytes) and the enlargement of existing fat cells throughout the body.Reducing caloric intake and increasing physical activity are often not sustainable and there are few safe alternative treatments. There are no treatments that take advantage of modern molecular medicine's advances in immunotherapy. Therapeutic applications of monoclonal antibodies (mAbs) offer a way to target treatments to specific tissues. However, despite substantial work showing that mAbs to adipocyte plasma membrane antigens (PMAs) may be used to suppress fat development in animal models, there are currently no mAbs for either therapeutic or diagnostic applications in human obesity. Thus, the immediate goal for this Phase I project is to use Abeome's rapid and efficient DiSH (Direct Selection of Hybridomas) technology to isolate a battery of mAbs specific for PMAs on the surface of human visceral preadipocytes and adipocytes. Our long-term goal is to develop immuno-therapeutics that offer a variety of adipocyte- targeted outcomes, such as stimulating transdifferentiation of white adipocytes to brown adipocytes, inhibiting adipogenesis, or inducing apoptosis. Our Phase I Specific Aims are as follows. #1. Immunize 20 mice with human visceral preadipocytes and identify 10 mice with the best antibody titers to PMAs of human visceral preadipocytes and adipocytes. #2. Isolate at least one hundred hybridomas making antibodies to human visceral preadipocytes and adipocytes using Abeome's DiSH-PMA protocol. #3. Using whole cell ELISAs and immunofluorescence microscopy (IFM) identify 20 mAb reagents that react with surface PMAs on human visceral preadipocytes and adipocytes but not with human adipocyte derived stem cells (ADSC), human mesenchymal stem cells (hMSC), human subcutaneous preadipocytes or adipocytes, or control cells from other human tissues. Abeome and its academic collaborators plan to submit a Phase II proposal to further develop adipocyte- specific mAbs as therapeutic, diagnostic and research agents. We will identify specific human mAbs that can be stably coupled to drug delivery agents and testedin vitro. The most appropriate drug delivery method will be tested in vivo to deliver a compound that stimulates transdifferentiation of white adipocytes to brown-like adipocytes or a compound that specifically inhibits adipogenesis or that induces apoptosis. Antibody targeted drug delivery will then be tested in appropriate animal models. The data generated in these studies will serve as the basis for clinical evaluation of this immuno-therapeutic approach to treating obesity. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Therapeutic and diagnostic applications of monoclonal antibodies (mAbs) offer a way to target treatments to specific tissues and more critically assess disease status; however, despite substantial work showing that mAbs specific for adipocytes may be used to suppress fat development in animal models, there are currently no mAbs for either therapeutic or diagnostic applications in human obesity. Thus, the immediate goal for this Phase I project is to use Abeome's rapid and efficient DiSH (Direct Selection of Hybridomas) technology to isolate mAbs specific for human preadipocytes and adipocytes. Our long-term goal is to develop immuno-therapeutics for the prevention and treatment of obesity.