Small molecules combination therapy using polypharmacology approach as a novel treatment paradigm for rare bone disease

Progressive Osseous Heteroplasia (POH:MIM#166350) is an ultra-rare genetic disease of heterotopic ossification (HO) that is associated with inactivating mutations in the GNAS1 gene, which encodes for Gαs, that acts downstream of many G-protein coupled receptors in activating adenyl cyclase.1 Clinically, POH presents during infancy with dermal and subcutaneous ossifications, which progress during childhood into skeletal muscles and deep connective and soft tissues (e.g., tendon, ligaments, fascia). Over time, these ossifications lead to joint stiffness, bone and joint fusions, and growth retardation of the affected limbs. The aberrant Hedgehog pathway (Hh) signaling leads to a rapid and progressive endochondral heterotopic ossification (EHO) in skeletal muscle and connective tissues as a hallmark of the POH. Therefore, there are no treatments for POH under clinical development that are acutely acting and/or supplied locally. Nostopharma seeks to address this need by creating locally administered, small volume, extended-release formulations of Hh inhibitors as a promising approach to achieve a therapeutic effect, dose, and toxicity reduction. The objective for this preclinical proof of concept is to demonstrate the feasibility of eliminating systemic drug exposure and repurposing of clinically tested and previously authorized inhibitors of endochondral bone formation, such as Hh signaling inhibitors, formulated in a proprietary way, to treat a rare genetic disease-POH. Hedgehog signaling (Hh) has a seminal role in mesenchymal progenitor fate choice and inappropriate differentiation into osteoblasts and ectopic bone formation in soft tissues. Although arsenic trioxide (ATO), a highly potent Hh inhibitor, can directly block osteogenesis, chronic or systemic delivery is not an option for POH patients due to recognized side effects in tissues that are not the intended target. To circumvent these restricting side effects, a proprietary formulation of ATO encapsulated in immunomodulatory nanoparticles will be tested. This proof of concept will involve screening of dose and frequency in vitro using POH mouse isolated subcutaneous progenitor cells.