Developing novel therapeutics for the treatment of mastocytosis

Executive Summary of Predicate SBIR Phase I Grant and Team The overall objective of our predicate SBIR Phase I grant, which started in June 2022, is to develop novel and potent compounds for treating mastocytosis. Mastocytosis is a rare set of diseases, characterized by the increased presence of mast cells in various tissues and organs. Patients suffering from mastocytosis often have diverse triggers that promote the activation of mast cells and subsequently the onset of debilitating symptoms, ranging from hives and abdominal pain to organ damage and life-threatening anaphylaxis. Although treatment options for mastocytosis patients exist, they are non-specific and are often limited to symptom alleviation and fail to adequately address the incapacitating and life-threatening prognoses mastocytosis patients face. Therefore, better therapies are urgently needed and NemaGen’s mission is to address this substantial need. Our cutting-edge technologies have, for the first time, identified a unique mast cell progenitor that is defined by its expression of the enzyme Carbonic anhydrase 1 (Car1). Carbonic anhydrases are a family of metabolic enzymes, known for their important roles in regulating pH and CO2 homeostasis. However, their role in mast cell development was unappreciated. NemaGen’s peer-reviewed and published findings have demonstrated that pharmacologically or genetically targeting Car1 is sufficient to prevent murine and human mast cell development. Moreover, we have shown that Car1 inhibition is sufficient to prevent mast cell responses in murine models of mastocytosis. Collectively, our exciting findings suggest that Car1 represents a new therapeutic target to treat mastocytosis and other mast cell-mediated diseases. We have developed a highly efficient drug discovery program, which is being accelerated with the assistance of our SBIR Phase I grant funding and funding from the venture capital arm of the New Jersey Health Foundation (NJHF). Since receiving our Phase I SBIR funding, we have engaged a leading medicinal chemist consultant to complement NemaGen’s established expertise in carbonic anhydrase enzymes and mast cell biology. This has resulted in the development of multiple lead compounds with more than 100-fold higher potency than established Car1 inhibitors (Table. 1) helping us to further advance our Phase 1 Aims. Overall, the specific aims of the proposed Phase I research were to: (1) Design, synthesize and optimize novel carbonic anhydrase inhibitors. (2) Evaluate the effects of Car enzyme inhibitors on enzymatic function and mast cell development. Our proposed I-Corps team will include the following three members. Member Names Role Nick Shubin, PhD NemaGen CEO Scott Alpizar, PhD Industry Expert, Venture Capitalist Jianya Peng, PhD PD/PI All three members are highly motivated and committed to the time requirements of the program.