Angioedema (AE) is a rare clinical symptom reported to affect at least 200,000 people in the US and approximately 1 in 30-50,000 persons worldwide. It is readily recognized as a usually asymmetrical, non- erythematous, non-pruritic, non-pitting, localized, transient, episodic swelling of a soft body area involving lax skin, oropharyngolaryngeal tissue and/or gastrointestinal wall. Chronically recurrent angioedema causes significant personal, domestic, social, and occupational disability and exposes patients to the risk of death due to suffocation. Angioedema includes: hereditary angioedema (HAE), which is attributed to complete genetic deficiency or functionally disruptive mutations in the C1 inhibitor (C1-INH) gene (located on chromosome 11q12-q13); drug-induced AE? which today is the fastest growing group of patients?which occurs in a segment of population under treatment with ACE-inhibitors; and idiopathic AE, which is of unknown origin. C1-INH is the major regulator of the key enzymes involved in both the complement and kinin/kallikrein (KKS) systems. Therefore its physical or functional absence leads to uncontrolled activation of both systems resulting in the overproduction by the KKS of a potent vasoactive peptide, bradykinin (BK)?the major mediator of the swelling. Although several therapeutic interventions for short-term or long-term treatments are available?including C1- INH replacement therapy?each treatment presents itself with major or minor deleterious side effects. More importantly, the current therapeutic agents only target downstream events long after the KKS has been triggered. Therefore, new therapeutic modalities that address these concerns and target upstream events are a much-needed and unmet challenge. The receptor for the globular heads of C1q, gC1qR, is the major zinc- dependent high affinity receptor for both high molecular weight kininogen (HK) and FXII, and plays a central role in the assembly and activation of the KKS. Blockade of gC1qR with mAb 74.5.2, which inhibits HK binding to endothelial cells, also prevents kinin generation and vascular permeability in vivo (US patent recently awarded). The proposed studies are therefore designed to accomplish three goals. First, to solve the crystal structures of gC1qR: (i) in complex with HK and/or HKH20; and with mAb 74.5.2, (ii) then, using an vitro model of vascular permeability, to asses the presence and the activity of the permeabilizing factor(s) in plasma samples obtained from various AE patients, and (iii) to examine the therapeutic potential of not only mAbs but also small peptide inhibitors (linear or cyclic)?identified from the structure-function studies and pre-screened in Aim II? in a mouse model of intravital microscopy. The results from these studies, in turn, will not only elucidate the structural, physiological, and molecular correlates involved in the induction or enhancement of vascular permeability during the attack phase of angioedema, but in the long term, full understanding of the role of gC1qR in the pathophysiology of this syndrome will provide a sound rationale for the design of novel therapeutic approaches for the prevention and treatment of hereditary or ACE-induced AE.
Angioedema is a rare (200,000 people in the US and 1 in 30-50,000 persons worldwide) but a deadly disorder, which affects all ethnic groups?with no recognizable racial or sex prediction?and causes significant personal, domestic, social, and occupational disability and, if it affects the upper respiratory system may cause death by suffocation. Although a number of therapeutic interventions for short-term or long-term treatments are available, each treatment is fraught with major or minor deleterious side effects. The aim of the present proposal is to develop a novel therapeutic options by targeting a key cellular upstream target called gC1qR, which is responsible for triggering the kinin system to generate a small molecule, called bradykinin, which is the cause of the swelling seen in all angioedema patients.
