A closed-loop cell therapy engineered to autonomously secrete activin A inhibitor protects from fibrodysplasia ossificans progressiva.

Engineered cell therapies present an opportunity for endogenous, site-specific production of therapeutic agents. Fibrodysplasia ossificans progressiva (FOP) is a morbid condition in which patients develop extensive heterotopic bony lesions in response to aberrant sensitivity to Activin A, through a mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (ACVR1 R206H). We designed a transposon plasmid containing the transgene encoding ActR2A-Fc, with expression controlled by the BMP-responsive element (BRE), which is pathologically activated upon exposure to Activin A in FOP cells. FOP-derived marrow cells modified with this plasmid exhibited closed-loop functionality, with increased ActR2A-Fc expression upon exposure to Activin A and reduced expression upon its withdrawal. Bone marrow transplantation of labeled engineered FOP marrow cells into FOP mice resulted in the trafficking of engineered cells to sites at risk of FOP and a reduction of heterotopic bony lesions. These data provide proof-of-concept and a blueprint for marrow-derived cell therapies across the disease spectrum.