Modified serpins for the treatment of bradykinin-mediated disease

Abstract

The present invention relates to modified serpins for use in the treatment of bradykinin-mediated diseases. The modified serine protease inhibitors (serpins) have mutations in one or more of the P4, P3, P2, P1 and P1′ residues of their reactive center loop, which mutations increase the serpin's inhibition of plasma kallikrein (PK) as compared to the corresponding unmodified serpin. The mutations in the modified serpins of the invention further ensure that serpins display substantially no inhibition of at least thrombin and activated protein C. A modified serpin of the invention further preferably shows increased inhibition of at least one of an active form of Factor XII (FXII) and plasmin as compared to the corresponding unmodified serpin, and, preferably, the serpin inhibits at least one of an active form of FXII and PK stronger than they are inhibited by C1 esterase inhibitor. Preferably the modified serpin is a modified α1-antitrypsin. The invention further pertains to nucleic acid molecule encoding the modified serpins of the invention, e.g. a gene therapy vector, and to pharmaceutical compositions comprising the modified serpins of the invention or such gene therapy vectors.