Treatment with orally administered CU06-1004 (also known as SAC-1004)—an endothelial dysfunction blocker—has been shown to alleviate vascular hyperpermeability in a murine model of hereditary angioedema (HAE) by inhibition of bradykinin (BK)-induced interendothelial cell gap formation.
The main cause of HAE is known to be an overrelease of the vasoactive peptide BK, which is associated with mutation in the SERPING1 gene. BK activates endothelial cells and increases vascular permeability through disruption in the endothelial barrier, which subsequently leads to angioedema that can affect the face, lips, extremities, larynx, and gastrointestinal tract. Many of the current treatments for HAE are limited in their availability and can impose a major economic burden on patients.
In an effort to identify additional therapeutic options for patients with HAE, the researchers sought to evaluate the effect of treatment with CU06-1004. To study the impact of the agent on BK-induced vascular hyperpermeability in vivo, they preadministered wild-type mice with CU06-1004, then induced vascular leakage via an intravenous (IV) injection of BK and observed the vascular alternation. Following this, they used SERPING1-deficient mice as an HAE murine model.
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In an in vitro model, the monolayer of human umbilical vein endothelial cells (HUVECs) was pretreated with SERPING1, then stimulated with BK. To study the protective effect of CU06-1004 against BK-induced endothelial hyperpermeability in vivo, an Evans Blue (EB) dye permeability assay was performed.
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To attain maximal BK-induced extravasation, the mice received an IV tail injection of a solution that contained BK and EB dye. CU06-1004 was administered orally 10 minutes prior to this injection. Quantitative analysis revealed that BK significantly increased EB dye extravasation in the ear, front foot, and back foot tissue; CU06-1004, on the other hand, significantly decreased extravasation.
Results of the study demonstrated that BK was linked to a disruption in the endothelial barrier and the formation of interendothelial cell gaps, which lead to hyperpermeability both in vivo and in vitro. Treatment with CU06-1004 was able to protect the endothelial barrier by suppression of Src, however, along with myosin light chain activation via BK, and thus alleviated hyperpermeability.
The authors concluded that “protecting endothelium against BK with CU06-1004 could serve as a potential prophylactic/therapeutic approach for [patients with HAE].”
Reference
Lee S, Kim Y, Kim Y-S, Zhang H, Noh M, Kwon Y-G. CU06-1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium. Allergy. Published online February 14, 2023. doi:10.1111/all.15674
