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Scientific Exploration in Hereditary Angioedema

Aiming to permanently rebalance the kallikrein-kinin system1 

About Hereditary Angioedema

Hereditary angioedema (HAE) causes recurrent, unpredictable, and potentially life-threatening swelling attacks in patients due to an imbalance in the kallikrein-kinin system and overproduction of bradykinin, which increases vascular permeability.2-5
An illustration showing hereditary angioedema (HAE)

B, bradykinin; C1-INH, C1 esterase inhibitor; KLKB1, kallikrein B1 gene that encodes plasma prekallikrein.

Therapeutic Landscape

Available on-demand and prophylactic modalities for treating HAE target kallikrein and/or bradykinin at the RNA and protein level.8,9 Investigational on-demand approaches similarly aim to target kallikrein and bradykinin at the protein level while investigational prophylactic approaches aim to expand modalities to target kallikrein at the RNA and DNA levels.10-12
An illustration showing the therapeutic landscape of hereditary angioedema (HAE)

C1-INH, C1 esterase inhibitor; DNA, deoxyribonucleic acid; FDA, US Food and Drug Administration; KLKB1, kallikrein B1 gene that encodes plasma prekallikrein; mRNA, messenger RNA; RNA, ribonucleic acid.

Rationale for CRISPR Research

HAE types 1 and 2 are caused by mutations in the SERPING1 gene that encodes the C1 esterase inhibitor protein, which leads to an imbalance in the kallikrein-kinin system due to the C1 esterase inhibitor’s inability to regulate it.5 However, the SERPING1 gene presents a significant challenge as a therapeutic target because of the multiple disease variants present across patients and the gene’s large size, which complicates the development of gene transfer approaches.8,15-17
Investigational CRISPR-based therapies are designed to introduce a small, precise edit to inactivate a particular disease-associated gene.1 Since SERPING1 already produces a nonfunctional protein in HAE types 1 and 2, it is not an ideal target for investigational CRISPR approaches.8
There may be other genes within the contact activation system that could be targeted by CRISPR to potentially treat HAE. For example, the KLKB1 gene encodes for prekallikrein, which ultimately leads to the production of bradykinin. Targeting the KLKB1 gene may potentially rebalance the system and lower bradykinin production.1 Bradykinin is the known mediator of swelling in patients with HAE, and targeting kallikrein itself is a clinically validated approach for preventing angioedema attacks.1
Since the kallikrein pathway is a clinically validated target and the primary source of kallikrein synthesis is the liver, investigational CRISPR technology aims to edit the KLKB1 gene with the goal of halting bradykinin production in HAE.1,18
Learn More About How CRISPR Works

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Our goal is to equip healthcare professionals with the essential knowledge to understand the science of CRISPR and its potential as a therapeutic option to support informed decision-making.

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  11. Press release. Pharvaris. December 6, 2023. Accessed March 12, 2025. https://ir.pharvaris.com/news-releases/news-release-details/pharvaris-announces-positive-top-line-phase-2-data-chapter-1
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