CU06-1004

Over‐release of the vasoactive peptide bradykinin (BK) due to mutation in the SERPING1 gene is the leading cause of hereditary angioedema (HAE). BK directly activates endothelial cells and increases vascular permeability by disrupting the endothelial barrier, leading to angioedema affecting face, lips, extremities, gastrointestinal tract, and larynx. Although various pharmacological treatment options for HAE became available during the last decade, they are presently limited and pose a major economic burden on patients. To identify additional therapeutic options for HAE, we evaluated the effect of CU06‐1004, an endothelial dysfunction blocker, on BK‐induced vascular hyperpermeability and the HAE murine model.

To investigate the effect of CU06‐1004 on BK‐induced vascular hyperpermeability in vivo, we pre‐administrated WT mice with the drug and then induced vascular leakage through intravenous injection of BK and observed vascular alternation. Then, SERPING1 deficient mice were used for a HAE murine model. For an in vitro model, the HUVEC monolayer was pre‐treated with CU06‐1004 and then stimulated with BK.

Bradykinin disrupted the endothelial barrier and formed interendothelial cell gaps, leading to hyperpermeability in vivo and in vitro. However, CU06‐1004 treatment protected the endothelial barrier by suppressing Src and myosin light chain activation via BK and alleviated hyperpermeability.

Our study shows that CU06‐1004 oral administration significantly reduced vascular hyperpermeability in the HAE murine model by protecting the endothelial barrier function against BK stimulation. Therefore, protecting endothelium against BK with CU06‐1004 could serve as a potential prophylactic/therapeutic approach for HAE patients.

Retinal vascular diseases are the leading cause of blindness worldwide. These diseases have common disease mechanisms including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation. Treatment of these diseases with laser therapy, anti-VEGF injections and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying cause of the pathology and may have harmful side effects. Pathological processes that damage retinal vessels result in vascular occlusion and impairment of the barrier properties of retinal endothelial cells, leading to excessive vascular leakage. Therefore, a new therapeutic approach is needed for the treatment of retinal vascular disease. We were able to confirm that oral administration of CU06-1004, an endothelial dysfunction blocker, inhibited retinal vascular leakage induced by vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). Interestingly, oral administration of CU06-1004 prevented excessive vascular leakage in the diabetic retinopathy model. In addition, CU06-1004 inhibited angiogenesis and confirmed vascular stabilization in the oxygen-induced retinopathy model and laser-induced CNV model. Taken together, CU06-1004 could be a potential therapeutic agent for the treatment of retinal vascular diseases.