Heart disease is one of the top causes of healthcare expenses in the United States. Lethal ventricular cardiac arrhythmia can arise in acquired or congenital heart disease. Long QT syndrome type 3 (LQT3) is a congenital form of ventricular arrhythmia caused by mutations in the cardiac sodium channel SCN5A. Mexiletine is a Class 1 antiarrhythmic drug that inhibits INa-L and shortens the QT interval in LQT3 patients. However, slightly above therapeutic doses, Mexiletine prolongs the cardiac action potential. Mexiletine was reengineered in an iterative process called dynamic medicinal chemistry to explore structure activity relationships (SAR) for AP shortening and prolongation of AP kinetics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Cancer is a multifaceted disease that is overwhelming in the breadth and scope of its genetic diversity, tissue pathology, and response to therapy. In recent years, the development of novel chimeric antigen receptor (CAR) containing cell-based therapies has provided significant clinical benefit to patients with certain hematological malignancies. The overall response rates (ORR) of Food and Drug Administration (FDA) approved autologous CD19 CAR T cell products for the treatment of refractory and relapsed B cell lymphomas have reached approximately 80% in defined patient populations, with durable remissions of greater than several years. Regrettably, the deployment of these novel cell-based therapies against solid tumor indications has garnered much less enthusiasm due to disappointing clinical success. The intrinsic adaptability of solid tumors makes them particularly elusive for effective targeted treatment, in part due to their extensive cellular heterogeneity and antigen diversity, their capacity to evade immune responses through antigen escape, and their ability to establish immune suppressive microenvironments. Identifying and selecting appropriate tumor specific antigens that distinguish tumor cells from healthy tissue remains arguably one of the most essential requirements to develop efficacious solid tumor targeting cell-based therapies.

Type II collagen (COL2A1) is the principal structural protein of cartilage and is crucial for maintaining extracellular matrix integrity during skeletal development. Pathogenic variants in COL2A1 disrupt collagen folding, secretion, and fibrillar assembly, leading to defective cartilage architecture and impaired chondrocyte maturation. These molecular alterations underline a broad group of autosomal dominant skeletal disorders collectively known as type II collagenopathies.