Recombinant Human Tissue Kallikrein-1 for Treating Acute Ischemic Stroke and Preventing Recurrence

Kasner, Scott E.; Bath, Philip M.; Hill, Michael D.; Volpi, John J.; Giuffre, Michael; Masuoka, Lorianne; Wambeke, David; Madeddu, Paolo R.

Abstract

Novel strategies are needed for the treatment of acute ischemic stroke when revascularization therapies are not clinically appropriate or are unsuccessful. Recombinant human tissue kallikrein-1 (rKLK1), a bradykinin-producing enzyme, offers a promising potential solution. In animal studies of acute stroke, there is a marked 36-fold increase in bradykinin B2 receptor on brain endothelial cells of the ischemic region. Due to this environment, rKLK1 generated bradykinin will exert a potent local vasodilation and increase brain perfusion via three synergistic signaling pathways downstream to the B2 receptor. Because of its preferential effect on ischemic tissue, systemic adverse effects such as hypotension are avoided with proper dosing. In addition, with initial vasodilation through recruitment of preexisting collaterals, rKLK1 promotes long-term benefit of brain perfusion by promoting new collateral formation. With an extended course of therapy for weeks after acute ischemic stroke, these multifaceted effects may also reduce the risk of stroke recurrence. A prior phase II trial demonstrated a favorable impact on clinical outcomes and recurrent strokes, particularly among patients who were not eligible for mechanical thrombectomy. A Phase II/III trial has launched in this population, though opportunities for combination for revascularization therapies deserve further investigation.

Citation

Kasner, S. E., Bath, P. M., Hill, M. D., Volpi, J. J., Giuffre, M., Masuoka, L., Wambeke, D., & Madeddu, P. R. (2025). Recombinant Human Tissue Kallikrein-1 for Treating Acute Ischemic Stroke and Preventing Recurrence. Stroke, https://doi.org/10.1161/STROKEAHA.124.048858

• Journal Article Type: Article
• Acceptance Date: Nov 25, 2024
• Online Publication Date: Jan 6, 2025
• Publication Date: Jan 6, 2025
• Deposit Date: Dec 9, 2024
• Publicly Available Date: Jul 7, 2025
• Journal: Stroke
• Print ISSN: 0039-2499
• Electronic ISSN: 1524-4628
• Publisher: American Heart Association
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1161/STROKEAHA.124.048858
• Keywords: bradykinin; cerebral infarction; kallikreins; stroke; vasodilation
• Public URL: https://nottingham-repository.worktribe.com/output/42831506
• Publisher URL: https://pubmed.ncbi.nlm.nih.gov/39758014/
• Additional Information: Published: 2025-01-06