Precision RNAi for fibrodysplasia ossificans progressiva in mice using a combinatorial unimolecular allele selective approach

Fibrodysplasia ossificans progressiva is a rare genetic disorder caused primarily by the ACVR1R206H mutation, resulting in debilitating heterotopic ossification triggered by inflammatory flare-ups. Here, we report a disease-modifying, allele-selective small interfering RNA targeting ACVR1R206H while preserving wildtype ACVR1 function. Docosanoic acid-conjugated ACVR1 small interfering RNA, alone or combined with one targeting the pro-inflammatory cytokine interleukin-1β, reduced heterotopic ossification in a murine model using both post-trauma and preventative strategies. Combination therapy was more effective than either pathway alone. We further developed lipophilic divalent molecules targeting both pathways in a single compound. These showed comparable muscle accumulation and efficacy to the combined monovalent forms following local and systemic administration, while enabling equimolar dosing and simplified manufacturing. Treatment suppressed inflammatory, WNT, Notch, Hedgehog, and transforming growth factor β signaling in fibroadipogenic progenitors, reducing cartilage, bone, and connective tissue formation. This work establishes a platform for disease-modifying therapies in this and other musculoskeletal disorders. Fibrodysplasia ossificans progressiva progressively transforms muscle and connective tissues into bone. Here, researchers developed a targeted siRNA therapy that blocks the mutant receptor and inflammation, greatly reducing abnormal bone formation in mice.