Methods: A subcutaneously administered small interfering RNA (siRNA) targeting factor XII (ALN-F12) was developed and initially tested in dose response and durability studies in mice. This compound was subsequently evaluated in a bradykinin-driven mouse model of vascular permeability. Animals received a single subcutaneous injection of either saline or 0.1, 0.3, 1, or 3 mg/kg of ALN-F12. One week later animals received the angiotensin converting enzyme (ACE) inhibitor captopril and Evans Blue dye via tail vein injections. Dye was extracted from tissue and blood samples to determine vascular permeability.
Results: A single subcutaneous administration of ALN-F12 led to potent, dose-dependent, and durable inhibition of factor XII. A single dose of 1 mg/kg resulted in >80% reduction of factor XII with effects durable for over 2 months. Similarly, administration of ALN-F12 resulted in dose-dependent reduction in ACE inhibitor induced vascular permeability, with doses ≥0.3 mg/kg resulting in normalization of vascular permeability to control levels.
Conclusions: These data suggest that the use of an RNAi therapeutic to inhibit factor XII is a potentially promising approach for the prophylactic treatment of hereditary angioedema.