Local bradykinin generation in hereditary angioedema☆,☆☆,★

In the past decade (2011–2020), there was a growing interest in the discovery and development of orphan drugs for the treatment of rare diseases. However, rare diseases only account for a population of 0.65‰–1‰ which usually occur with previously unknown biological mechanisms and lack of specific therapeutics, thus to increase the demands for the first-in-class (FIC) drugs with new biological targets or mechanisms. Considering the achievements in the past 10 years, a total of 410 drugs were approved by U.S. Food and Drug Administration (FDA), which contained 151 FIC drugs and 184 orphan drugs, contributing to make up significant numbers of the approvals. Notably, more than 50% of FIC drugs are developed as orphan drugs and some of them have already been milestones in drug development. In this review, we aim to discuss the FIC small molecules for the development of orphan drugs case by case and highlight the R&D strategy with novel targets and scientific breakthroughs.

Hereditary angioedema (HAE) is a rare, chronic, genetic disease that presents with nonpruritic angioedema of the face, extremities, airway (can be life-threatening), genitourinary system, and abdomen. These symptoms can significantly impair daily activities. Hereditary angioedema is classified into HAE owing to a deficiency of functional C1INH (HAE-C1INH) or HAE with normal C1INH (HAE-nl-C1INH). Both type I and II HAE-C1INH result from inherited or spontaneous mutations in the SERPING1 gene, which encodes for C1INH. These mutations result in C1INH dysfunction, leading to uncontrolled plasma kallikrein activity with excessive bradykinin production. Bradykinin receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in submucosal angioedema through fluid extravasation. Hereditary angioedema nl-C1INH is caused by either a known or unknown genetic mutation. The underlying mechanism of HAE-nl-C1INH is less well understood but is thought to be related to bradykinin signaling. Plasma kallikrein inhibitors have been developed to inhibit the kallikrein-kinin pathway to prevent (prophylactic) and treat on-demand (acute) HAE attacks. Several of these medications are delivered through subcutaneous or intravenous injection, although new and emerging therapies include oral formulations. This article provides a historical review and describes the evolving landscape of available kallikrein inhibitors to treat HAE-C1INH.

Patients with urticaria and angioedema often have triggers that cause an outbreak or a swelling episode or worsen their chronic condition. Exploring these factors with each patient may result in better understanding and control of their disease. Patients should be advised to avoid known triggers, if feasible, or prepare to prevent or control an exacerbation with appropriate pretreatment if avoidance is not possible. In this review, we describe and discuss a variety of factors for which there is evidence that they cause or exacerbate chronic spontaneous urticaria and angioedema. These potentially exacerbating factors include drugs, food additives, and naturally occurring pseudoallergens, mental stress, and trauma.

Remarkable advances in nano delivery systems have provided new hope for tumor prevention, diagnosis and treatment. However, only limited clinical therapeutic effects against solid tumors were achieved. One of the main reasons is the presence of abundant physiological and pathological barriers in vivo that impair tumoral penetration and distribution of the nanodrugs. These barriers are related to the components of tumor microenvironment (TME) including abnormal tumor vasculature, rich composition of the extracellular matrix (ECM), and abundant stroma cells. Herein, we review the advanced strategies of TME remodeling to overcome these biological obstacles against nanodrug delivery. This review aims to offer a perspective guideline for the implementation of promising approaches to facilitate intratumoral permeation of nanodrugs through alleviation of biological barriers. At the same time, we analyze the advantages and disadvantages of the corresponding methods and put forward possible directions for the future researches.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.

An impairment of the endothelial barrier function underlies a wide spectrum of pathological conditions. Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) can be considered the “pathophysiological and clinical paradigm” of Paroxysmal Permeability Diseases (PPDs), conditions characterized by recurrent transient primitively functional alteration of the endothelial sieving properties, not due to inflammatory-ischemic-degenerative injury and completely reversible after the acute flare. It is a rare yet probably still underdiagnosed disease which presents with localized, non-pitting swelling of the skin and submucosal tissues of the upper respiratory and gastrointestinal tracts, without significant wheals or pruritus. The present review addresses the pathophysiology of C1-INH-HAE with a focus on the crucial role of the endothelium during contact and kallikrein/kinin system (CAS and KKS) activation, currently available and emerging biomarkers, methods applied to get new insights into the mechanisms underlying the disease (2D, 3D and in vivo systems), new promising investigation techniques (autonomic nervous system analysis, capillaroscopy, flow-mediated dilation method, non-invasive finger plethysmography). Hints are given to the binding of C1-INH to endothelial cells. Finally, crucial issues as the local vs systemic nature of CAS/KKS activation, the episodic nature of attacks vs constant C1-INH deficiency, pros and cons as well as future perspectives of available methodologies are briefly discussed.