title: Inhibition of vascular permeability by antisense-mediated inhibition of plasma kallikrein and coagulation factor 12.
abstract: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent, acute, and painful episodes of swelling involving multiple tissues. Deficiency or malfunction of the serine protease inhibitor C1 esterase inhibitor (C1-INH) results in HAE types 1 and 2, respectively, whereas mutations in coagulation factor 12 (f12) have been associated with HAE type 3. C1-INH is the primary inhibitor of multiple plasma cascade pathways known to be altered in HAE patients, including the complement, fibrinolytic, coagulation, and kinin-kallikrein pathways. We have selectively inhibited several components of both the kinin-kallikrein system and the coagulation cascades with potent and selective antisense oligonucleotides (ASOs) to investigate their relative contributions to vascular permeability. We have also developed ASO inhibitors of C1-INH and characterized their effects on vascular permeability in mice as an inducible model of HAE. Our studies demonstrate that ASO-mediated reduction in C1-INH plasma levels results in increased vascular permeability and that inhibition of proteases of the kinin-kallikrein system, either f12 or prekallikrein (PKK) reverse the effects of C1-INH depletion with similar effects on both basal and angiotensin converting enzyme (ACE) inhibitor-induced permeability. In contrast, inhibition of coagulation factors 11 (f11) or 7 (f7) had no effect. These results suggest that the vascular defects observed in C1-INH deficiency are dependent on the kinin-kallikrein system proteases f12 and PKK, and not mediated through the coagulation pathways. In addition, our results highlight a novel therapeutic modality that can potentially be employed prophylactically to prevent attacks in HAE patients.
authors.affiliation: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California 92010, USA. gbhattac@isisph.com
authors.forename: Gourab
authors.initials: G
authors.lastname: Bhattacharjee
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Revenko
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Crosby
authors.forename: Chris
authors.initials: C
authors.lastname: May
authors.forename: Dacao
authors.initials: D
authors.lastname: Gao
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
mesh_terms: D054179:Angioedemas, Hereditary / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D050718:Complement C1 Inhibitor Protein; D004195:Disease Models, Animal; D005167:Factor VII / Q000378:metabolism; D005172:Factor XI / Q000378:metabolism; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007279:Injections, Subcutaneous; D007705:Kinins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011288:Prekallikrein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D050718:Complement C1 Inhibitor Protein; D007705:Kinins; D016376:Oligonucleotides, Antisense; D005167:Factor VII; D005174:Factor XII; D005172:Factor XI; D011288:Prekallikrein; D020842:Plasma Kallikrein