Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

Busse, Paula J.; Kaplan, Allen P.

doi:10.1016/j.jaip.2021.11.011

Cited by 22 publications

(19 citation statements)

References 72 publications

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“…Furthermore, we found that CU06-1004 treatment repressed BK-induced Src kinase and MLC activation. These findings showed that CU06-1004 pre- [38][39][40] However, a drug for HAE that targets endothelial integrity has not yet been developed. Although all currently marketed drugs show efficacy in controlling symptoms, most require IV or subcutaneous injection for administration, which is not only inconvenient to patients but also causes side effects including bleeding, rash, infection, inflammation, and itching at the injection site.…”

Section: Discussionmentioning

confidence: 99%

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CU06‐1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium

Lee

Kim

et al. 2023

Allergy

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Background: 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. Methods: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.Results: 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. Conclusion: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.

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Section: Discussionmentioning

confidence: 99%

“…Over the last decade, therapeutic options for HAE have shown notable progress. The major mechanisms of currently marketed drugs are C1‐INH replacement, kallikrein inhibition, BK receptor antagonism, and androgen 38–40 . However, a drug for HAE that targets endothelial integrity has not yet been developed.…”

Section: Discussionmentioning

confidence: 99%

CU06‐1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium

Lee

Kim

et al. 2023

Allergy

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“…Excessive bradykinin production or heightened vascular sensitivity to bradykinin appears to underlie HAE [19 ▪ ,21 ▪ ]. Angioedema in the most common forms of HAE responds to FXIIa-neutralizing antibodies [22], PKa inhibitors [23] and reduction of plasma prekallikrein [24], attesting to the importance of the KKS in the disease process.…”

Section: Disease Processes Involving Factor XIImentioning

confidence: 99%

Recent advances in factor XII structure and function

Shamanaev

Litvak

Gailani

2022

Current Opinion in Hematology

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Purpose of review Factor XII (FXII), the precursor of the protease FXIIa, contributes to pathologic processes including angioedema and thrombosis. Here, we review recent work on structure-function relationships for FXII based on studies using recombinant FXII variants. Recent findings FXII is a homolog of pro-hepatocyte growth factor activator (Pro-HGFA). We prepared FXII in which domains are replaced by corresponding parts of Pro-HGA, and tested them in FXII activation and activity assays. In solution, FXII and prekallikrein undergo reciprocal activation to FXIIa and kallikrein. The rate of this process is restricted by the FXII fibronectin type-2 and kringle domains. Pro-HGA replacements for these domains accelerate FXII and prekallikrein activation. When FXII and prekallikrein bind to negatively charged surfaces, reciprocal activation is enhanced. The FXII EGF1 domain is required for surface binding. Summary We propose a model in which FXII is normally maintained in a closed conformation resistant to activation by intramolecular interactions involving the fibronectin type-2 and kringle domains. These interactions are disrupted when FXII binds to a surface through EGF1, enhancing FXII activation and prekallikrein activation by FXIIa. These observations have important implications for understanding the contributions of FXII to disease, and for developing therapies to treat thrombo-inflammatory disorders.

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“…Treatment with icatibant also decreased bradykinin levels in patients with HAE, but changes in plasma bradykinin levels were not directly related to the degree of symptom relief ( 58 ). Working upstream from icatibant, plasma kallikrein inhibitors block the binding site of kallikrein to prevent cleavage of HMW kininogen and subsequent bradykinin release and also reduce further activation of factor XIIa to disrupt the positive feedback loop that would otherwise lead to increased kallikrein production ( Figure 2 ) ( 16 , 33 , 59 , 60 ).…”

Section: Single Pathway Therapiesmentioning

confidence: 99%

Treatment of hereditary angioedema—single or multiple pathways to the rescue

Valerieva

Longhurst

2022

Front. Allergy

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Hereditary angioedema (HAE) is a rare disease caused by mutations in the SERPING1 gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Current options for the treatment and prevention of HAE attacks include treating all affected pathways via direct C1-INH replacement therapy; or specifically targeting components of the contact activation system, in particular by blocking the bradykinin B2 receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and recombinant human C1-INH have demonstrated efficacy and safety for treatment of HAE attacks, although time to onset of symptom relief varied among trials, specific agents, and dosing regimens. Data from retrospective and observational analyses support that short-term prophylaxis with intravenous C1-INH products can help prevent HAE attacks in patients undergoing medical or dental procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH significantly decreased the HAE attack rate vs. placebo, although breakthrough attacks were observed. Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Icatibant, administered for treatment of angioedema attacks, reduced B2R-mediated vascular permeability and, compared with placebo, reduced the time to initial symptom improvement. Plasma kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein to prevent cleavage of high molecular weight kininogen and subsequent bradykinin generation. Ecallantide was shown to be efficacious for HAE attacks and is licensed for this indication in the United States, but the labeling recommends that only health care providers administer treatment because of the risk of anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein inhibitors lanadelumab and berotralstat are recommended as first-line options for long-term prophylaxis and have demonstrated marked reductions in HAE attack rates. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient.

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Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

Cited by 22 publications

References 72 publications

CU06‐1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium

CU06‐1004 alleviates vascular hyperpermeability in a murine model of hereditary angioedema by protecting the endothelium

Recent advances in factor XII structure and function

Treatment of hereditary angioedema—single or multiple pathways to the rescue

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