An Investigational RNAi Therapeutic Targeting Factor XII (ALN-F12) for the Treatment of Hereditary Angioedema

Rationale: Hereditary angioedema is a genetic disorder caused by a defect in the C1-inhibitor gene that results in poor control of contact pathway activation and bradykinin generation.  Excessive bradykinin generation increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of hereditary angioedema.  We hypothesized that the use of RNA interference (RNAi) to target factor XII would reduce contact pathway activation and prevent excessive bradykinin generation.

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.