IONIS-PKK Rx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production

Nucleic Acid Ther. 2019 Apr;29(2):82-91. doi: 10.1089/nat.2018.0754. Epub 2019 Feb 28.


Kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by C1-esterase inhibitor (C1-INH). In hereditary angioedema (HAE), genetic mutations result in deficient or dysfunctional C1-INH and dysregulation of the contact system leading to recurrent, sometimes fatal, angioedema attacks. IONIS-PKKRx is a second-generation 2'-O-(2-methoxyethyl)-modified chimeric antisense oligonucleotide, designed to bind and selectively reduce prekallikrein (PKK) mRNA in the liver. IONIS-PKKRx demonstrated dose-dependent reduction of human prekallikrein hepatic mRNA and plasma protein in transgenic mice and dose- and time-dependent reductions of plasma PKK in Cynomolgus monkeys. Similar dose-dependent reductions of plasma PKK levels were observed in healthy human volunteers accompanied by decreases in bradykinin generation capacity with an acceptable safety and tolerability profile. These results highlight a novel and specific approach to target PKK for the treatment of HAE and other diseases involving contact system activation and overproduction of bradykinin.

Keywords: antisense oligonucleotide; hereditary angioedema; plasma prekallikrein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angioedemas, Hereditary / blood
  • Angioedemas, Hereditary / genetics
  • Angioedemas, Hereditary / therapy*
  • Animals
  • Animals, Genetically Modified / blood
  • Bradykinin / blood
  • Bradykinin / genetics*
  • Complement C1 Inhibitor Protein / pharmacology
  • Complement C1s / antagonists & inhibitors
  • Complement C1s / genetics*
  • Dose-Response Relationship, Drug
  • Healthy Volunteers
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Macaca fascicularis / blood
  • Mice
  • Oligodeoxyribonucleotides, Antisense / genetics
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Prekallikrein / antagonists & inhibitors
  • Prekallikrein / genetics*


  • Complement C1 Inhibitor Protein
  • Oligodeoxyribonucleotides, Antisense
  • Prekallikrein
  • Complement C1s
  • Bradykinin