Plasma prekallikrein messenger RNA (PKK mRNA) (PKK mRNA)

Plasma prekallikrein (PKK) mRNA is the transcript of the KLKB1 gene, which encodes the zymogen precursor of the serine protease plasma kallikrein (UniProt P03952). Plasma kallikrein is a key component of the contact activation system and the kallikrein-kinin cascade, where it cleaves high-molecular-weight kininogen (HMWK) to release bradykinin, a potent vasodilator (NCBI Gene ID: 3818). In hereditary angioedema (HAE), the dysregulation of this pathway leads to excessive bradykinin production, resulting in localized edema and life-threatening airway obstruction (Fiedler et al., 2021). PKK mRNA has emerged as a significant therapeutic target for antisense oligonucleotides (ASOs) like donidalorsen, which bind to the mRNA and trigger its degradation via RNase H1 (Ionis Pharmaceuticals, 2024). By reducing the levels of PKK mRNA, these therapies lower the circulating levels of prekallikrein protein, thereby preventing the cascade that leads to HAE attacks. This target is particularly attractive because individuals with natural prekallikrein deficiency (Fletcher trait) are generally asymptomatic, suggesting that long-term suppression of the target is well-tolerated (StatPearls, 2023). Clinical trials have demonstrated that targeting PKK mRNA provides a robust prophylactic effect, significantly reducing the frequency of angioedema attacks in patients (Fiedler et al., 2021). The use of ligand-conjugated antisense technology (LICA) allows for specific delivery to the liver, the primary site of prekallikrein synthesis, enhancing potency and safety (Ionis Pharmaceuticals, 2024).

Other names

KLKB1 mRNAPrekallikrein mRNAFletcher factor mRNAPlasma kallikrein B1 mRNA

Antisense oligonucleotide-mediated degradation of the target mRNA via RNase H1, which prevents the translation of the plasma prekallikrein protein (Fiedler et al., 2021).