Prevention of heterotopic ossification with localized delivery of arsenic trioxide loaded nanoparticles as a novel treatment for fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disease that affects around 1 in 1.5–2.0 million live births, in which a point mutation in ACVR1, encoding the type 1 abnormal bone morphogenetic protein (BMP) receptor ALK2, causes aberrant BMP signaling. The aberrant signaling leads to a rapid and progressive endochondral heterotopic ossification (EHO) in skeletal muscle and connective tissues as a hallmark of the FOP. All of FOP preventative drugs have a systemic application and are used chronically to lessen the risk of flare-ups and/or the development of new EHO. Therefore, there are no treatments for FOP 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 Hedgehog pathway (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-FOP. 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 FOP 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 was developed. This proof of concept will involve screening of dose and frequency of intramuscular administration required to significantly reduce intramuscular EHO in an Avcr1R206H expressing mouse model of FOP.