The KLKB1 gene encodes prekallikrein (PK), which is activated into kallikrein, a central component of the kallikrein-kinin system (KKS). Kallikrein's primary role is to cleave high-molecular-weight kininogen (HMWK) to produce the highly potent vasoactive peptide, bradykinin. Bradykinin is a critical regulator of vasodilation, vascular permeability, and blood pressure, also playing a role in inflammation, pain perception, and coagulation.

While loss-of-function mutations in KLKB1 typically lead to asymptomatic prekallikrein deficiency, gain-of-function mutations are far more clinically significant. These mutations are strongly associated with hereditary angioedema (HAE), a rare autosomal dominant disorder. A specific mutation, such as p.Glu420Lys, makes prekallikrein more easily activated, leading to an overproduction of bradykinin. Excess bradykinin causes a sharp increase in vascular permeability, resulting in severe, recurrent swelling in various parts of the body, including the skin, gastrointestinal tract, and upper airways. Laryngeal swelling, in particular, poses a major risk of airway obstruction and asphyxiation, making it the primary cause of death in HAE patients.

Since 2008, the FDA has approved 11 therapies for HAE, with three of the most recent occurring in the past two months, two of which target the key KLKB1 pathway ^[2]. Historically, treatments for HAE focused on managing acute attacks, primarily with injectable peptides or small-molecule inhibitors that had a relatively short duration of action.

The approval of Berotralstat on December 3, 2020, marked a significant milestone. As a once-daily oral small-molecule inhibitor, it offers a preventive approach to HAE attacks. The HAE market has seen a rapid shift towards oral therapies, with a compound annual growth rate (CAGR) of 20.10%, largely driven by Berotralstat's success. In 2024, its sales reached $437 million, with a 51% year-over-year increase in the first quarter of 2025 ^[4].

The recent approvals of Sebetralstat and Donidalorsen represent the next frontier in KLKB1-targeted drugs. Sebetralstat is an oral small-molecule inhibitor primarily for on-demand, acute treatment. It is the first new on-demand HAE therapy approved in over a decade, and the first and only oral on-demand therapy for the disease. Donidalorsen, on the other hand, is the first RNA-targeting therapy for HAE ^[2], using antisense oligonucleotide (ASO) technology for preventive treatment with a single injection every four weeks. These approvals signal a clear trend towards more effective and convenient treatments.

The future of KLKB1 therapy is now focused on next-generation, long-acting treatments. Lonvoguran (lonvo-z), a one-time gene editing therapy, is in Phase III clinical trials, aiming to permanently inactivate the KLKB1 gene and fundamentally shift HAE treatment from chronic management to a one-time cure. Top-line data from this trial is expected in the first half of 2026. Additionally, monoclonal antibody and siRNA therapies are also in Phase III trials ^[5]. KLKB1 drugs have become a core driving force in the HAE treatment field, pushing a fundamental shift from reactive, high-burden treatment to a proactive, low-burden, and high-efficiency approach.

The development of next-generation, long-acting therapies like gene therapies and siRNAs requires reliable preclinical models. Cyagen has developed the B6-huKLKB1 humanized mouse model (Product ID: C001845) as a crucial tool for research and drug development. This model effectively simulates human disease and drug mechanisms, making it an ideal platform for evaluating the efficacy and safety of novel therapies.

(See detailed data in the product manual).

1. Gene Expression Detection
   RT-qPCR analysis showed significant expression of the human KLKB1 gene and no expression of the mouse Klkb1 gene in the liver and kidneys of homozygous B6-huKLKB1 mice.
   
   Figure 3. Gene expression detection in the liver and kidney of 6-week-old homozygous B6-huKLKB1 mice and wild-type (WT) mice.
2. Protein Expression Detection (ELISA)
   ELISA results demonstrated that B6-huKLKB1 mice successfully express the human Prekallikrein 1B protein. Under normal physiological conditions, the protein encoded by KLKB1 is an inactive zymogen that is cleaved into its active form, Kallikrein 1B, only upon specific stimuli (e.g., activation by coagulation factor XIIa).
3.  
   
   Figure 4. Protein expression detection in the serum of B6-huKLKB1 mice and wild-type (WT) mice (6 weeks old, homozygous, n=3).
4. Lipid Metabolism & Liver Function
   Blood biochemistry results showed no significant differences in TC, TG, HDL-C, LDL-C, ALT, or AST levels between homozygous B6-huKLKB1 mice and WT mice, despite lower LDL-C levels in the humanized model (Bars represent mean ± SD, n=3).
   
   Figure 5. Lipid metabolism and liver function markers in the serum of 6-week-old homozygous B6-huKLKB1 mice and wild-type (WT) mice.

The B6-huKLKB1 mouse model (Product ID: C001845) is a crucial preclinical platform. By precisely replacing the mouse gene with the full-length human KLKB1 gene, the model successfully mimics human target expression at both the gene and protein levels. This makes it an ideal tool for studying the pathological functions of KLKB1 in both prekallikrein deficiency and HAE. The model provides a more human-relevant platform for evaluating the efficacy and safety of targeted therapies like siRNA and long-acting gene therapies, helping to accelerate the development of the next generation of HAE treatments.

At Cyagen, our capabilities extend far beyond models. We offer comprehensive Gene Therapy services to support your research from end to end, including our cutting-edge AI-powered AAV Discovery platform. Furthermore, our commitment to advancing rare disease research is exemplified by our collaboration with the Tsinghua-GD Rare Disease Drug Creation Center (RDDC), a platform dedicated to accelerating the translation of innovative rare disease therapies.

1. Fierce Pharma. KalVista bounces back from delay with FDA approval for oral rare disease med Ekterly. [Internet]. Silver Spring, MD: Questex; 2025 Aug 27 [cited 2025 Aug 28].
2. Fierce Pharma. Crowded HAE market steps up for Ionis after FDA nod for Dawnzera. [Internet]. Silver Spring, MD: Questex; 2025 Aug 27 [cited 2025 Aug 28].
3. Wisniewski P, Gangnus T, Burckhardt BB. Recent advances in the discovery and development of drugs targeting the kallikrein-kinin system. J Transl Med. 2024 Apr 26;22(1):388. doi: 10.1186/s12967-024-05216-5. PMID: 38671481; PMCID: PMC11046790.
4. Mordor Intelligence. Hereditary Angioedema Therapeutics Market Size, Share & Industry Outlook- 2030 [Internet]. Hyderabad, India: Mordor Intelligence.
5. Cohn DM, Renné T. Targeting factor XIIa for therapeutic interference with hereditary angioedema. J Intern Med. 2024 Oct;296(4):311-326. doi: 10.1111/joim.20008. PMID: 39331688.