Scientific exploration in HAE
Angioedema attacks occur in patients with hereditary angioedema (HAE) when excess bradykinin causes an increase in vascular permeability and fluid extravasation.1,14 Existing small-molecule drugs and biologics aim to bind with relevant proteins to help inhibit the subsequent release of bradykinin, while plasma-derived and recombinant C1-INH therapies aim to replace a missing protein.1
A new potential therapeutic target for HAE
Plasma prekallikrein (PKK), a key effector in the kallikrein-kinin system that acts downstream of activated factor XII and upstream of kallikrein and bradykinin, represents a unique HAE target.12
The kallikrein-kinin pathway19
In patients with HAE types I and II, genetic variants lead to deficiency or dysfunction of C1 inhibitor (C1-INH) activity, respectively. This protease inhibitor negatively regulates activated factor XII (FXIIa) and plasma kallikrein, and when its function is reduced or lost, results in an overproduction of bradykinin.13,15
In the absence of sufficient or functional C1-INH, FXIIa activates plasma prekallikrein (PKK) to form plasma kallikrein15
Plasma kallikrein then cleaves high-molecular-weight kininogen to release proinflammatory vasodilator peptide bradykinin1,15
Bradykinin binds to B2 receptors resulting in angioedema1
A positive feedback loop of plasma kallikrein generates additional FXIIa, which can then lead to further activation of the pathway16
New technologies offer the potential to address the disease in unique ways12,13
The science behind RNA-targeted medicines17
An established platform and class of medicines, RNA-targeted therapeutic strategies aim to directly regulate disease-causing genes and their variants. They selectively target a single gene product and are thus designed to alter gene expression without altering a patient’s genome.
By enabling modulation of the cell’s protein production, they regulate gene expression before translation of a protein even begins. Unlike gene therapy, RNA-targeted medicines are reversible.
An established modality, RNA-targeted medicines have been approved by the FDA to treat a variety of conditions, such as kidney, liver, cardiovascular, neurological, neuromuscular, and rare diseases, among others.17
RNA-targeted medicines contain several chemical modifications and features that enhance their therapeutic potential18:
- A phosphorothioate modification that increases stability
- A sugar modification that enhances pharmacokinetic and pharmacodynamic properties
- Sequence-specific base pairing to target mRNA
RNA-targeted medicines can leverage ligand-conjugated antisense (LICA) technology (eg, GaINAc), which adds specific chemical structures or molecules to allow for receptor-mediated delivery of the RNA-targeted medicine to a particular organ or tissue, for instance hepatic parenchymal cells.18
Additional exploratory approaches in HAE13,15
– Small-molecule competitive antagonists that aim to target disease-causing proteins
– Additional monoclonal antibodies that aim to target disease-causing proteins
– Gene therapies that aim to modify DNA
