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Targeting Factor 12 (F12) with a Novel RNAi Delivery Platform As a Prophylactic Treatment for Hereditary Angioedema (HAE)
Monday, March 7, 2016
South Exhibit Hall H (Convention Center)
Stacey Melquist, Darren Wakefield, Holly Hamilton, Qili Chu, Aaron Almeida, Lauren Almeida, Megan Walters, Jessica Montez, Julia Hegge, Jason Klein, Christine Hazlett, Tracie Milarch, Stephanie Bertin, Aaron Andersen, Edie Doss, Rachael Schmidt, Linda Goth, Sheryl Ferger, David Rozema, James Hamilton, David Lewis, Steven Kanner
Rationale:  A significant medical need exists for improved prophylactic treatment options for Hereditary Angioedema (HAE).  Factor 12 (F12) autoactivation in the absence of C1 inhibitor (C1INH) initiates the pathway that leads to bradykinin-mediated edema. We hypothesized that an RNA interference (RNAi) based approach for reducing liver F12 production using our Dynamic Polyconjugate (DPC)™ delivery platform may provide a new prophylactic therapy for HAE.

Methods:  Highly specific and mouse/human/non-human primate (NHP) cross-reactive RNAi triggers were designed in silico and screened for F12 knockdown activity in vitroand in wild type mice.  Structure activity relationship (SAR) studies of the most active RNAi triggers identified optimal modifications enabling lead identification. This lead RNAi trigger was further tested for activity and safety in NHPs. Disease-modifying activity in relevant disease-specific mouse models was also explored.

Results:  Screening of in vitro-active F12 RNAi triggers in wild type mice identified those triggers that exhibited significant and sustained knockdown of serum F12 levels.  SAR studies allowed identification of a lead RNAi trigger that demonstrated >97% maximum knockdown after a single 2 mg/kg dose.  A multi-dose study in NHPs using 2 mg/kg monthly doses showed >90% sustained knockdown of serum F12 levels without toxicity. NHPs in these studies showed changes in coagulation measurements consistent with F12 deficiency.  Studies in mice showed reduced FeCl3-induced thromboembolism consistent with the expected physiological effects of F12 knockdown. Studies in C1INH-deficient mice (HAE model) are currently in progress.

Conclusions: Delivery of a potent F12-specific RNAi trigger by DPC™ offers potential for a novel, infrequently-dosed prophylactic treatment for HAE.