Complement in Thrombotic Microangiopathies: Unraveling Ariadne's Thread Into the Labyrinth of Complement Therapeutics

Thrombotic microangiopathies (TMAs) are a heterogeneous group of syndromes presenting with a distinct clinical triad: microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. We currently recognize two major entities with distinct pathophysiology: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Beyond them, differential diagnosis also includes TMAs associated with underlying conditions, such as drugs, malignancy, infections, scleroderma-associated renal crisis, systemic lupus erythematosus (SLE), malignant hypertension, transplantation, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and disseminated intravascular coagulation (DIC). Since clinical presentation alone is not sufficient to differentiate between these entities, robust pathophysiological features need to be used for early diagnosis and appropriate treatment. Over the last decades, our understanding of the complement system has evolved rapidly leading to the characterization of diseases which are fueled by complement dysregulation. Among TMAs, complement-mediated HUS (CM-HUS) has long served as a disease model, in which mutations of complement-related genes represent the first hit of the disease and complement inhibition is an effective and safe strategy. Based on this knowledge, clinical conditions resembling CM-HUS in terms of phenotype and genotype have been recognized. As a result, the role of complement in TMAs is rapidly expanding in recent years based on genetic and functional studies. Herein we provide an updated overview of key pathophysiological processes underpinning complement activation and dysregulation in TMAs. We also discuss emerging clinical challenges in streamlining diagnostic algorithms and stratifying TMA patients that could benefit more from complement modulation. With the advent of next-generation complement therapeutics and suitable disease models, these translational perspectives could guide a more comprehensive, disease- and target-tailored complement intervention in these disorders

From Orphan Drugs to Adopted Therapies: Advancing C3-Targeted Intervention to the Clinical Stage

Complement dysregulation is increasingly recognized as an important pathogenic driver in a number of clinical disorders. Complement-triggered pathways intertwine with key inflammatory and tissue destructive processes that can either increase the risk of disease or exacerbate pathology in acute or chronic conditions. The launch of the first complement-targeted drugs in the clinic has undeniably stirred the field of complement therapeutic design, providing new insights into complement\u27s contribution to disease pathogenesis and also helping to leverage a more personalized, comprehensive approach to patient management. In this regard, a rapidly expanding toolbox of complement therapeutics is being developed to address unmet clinical needs in several immune-mediated and inflammatory diseases. Elegant approaches employing both surface-directed and fluid-phase inhibitors have exploited diverse components of the complement cascade as putative points of therapeutic intervention. Targeting C3, the central hub of the system, has proven to be a promising strategy for developing biologics as well as small-molecule inhibitors with clinical potential. Complement modulation at the level of C3 has recently shown promise in preclinical primate models, opening up new avenues for therapeutic intervention in both acute and chronic indications fueled by uncontrolled C3 turnover. This review highlights recent developments in the field of complement therapeutics, focusing on C3-directed inhibitors and alternative pathway (AP) regulator-based approaches. Translational perspectives and considerations are discussed, particularly with regard to the structure-guided drug optimization and clinical advancement of a new generation of C3-targeted peptidic inhibitors

Complement-Dependent Mechanisms and Interventions in Periodontal Disease

Periodontitis is a prevalent inflammatory disease that leads to the destruction of the tooth-supporting tissues. Current therapies are not effective for all patients and this oral disease continues to be a significant public health and economic burden. Central to periodontal disease pathogenesis is a reciprocally reinforced interplay between microbial dysbiosis and destructive inflammation, suggesting the potential relevance of host-modulation therapies. This review summarizes and discusses clinical observations and pre-clinical intervention studies that collectively suggest that complement is hyperactivated in periodontitis and that its inhibition provides a therapeutic benefit. Specifically, interception of the complement cascade at its central component, C3, using a locally administered small peptidic compound (Cp40/AMY-101) protected non-human primates from induced or naturally occurring periodontitis. These studies indicate that C3-targeted intervention merits investigation as an adjunctive treatment of periodontal disease in humans

Clinical promise of next-generation complement therapeutics

The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious cycle of inflammatory damage that exacerbates pathology. The clinical merit of targeting the complement system has been established for rare clinical disorders such as paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Evidence from preclinical studies and human genome-wide analyses, supported by new molecular and structural insights, has revealed new pathomechanisms and unmet clinical needs that have thrust a new generation of complement inhibitors into clinical development for a variety of indications. This review critically discusses recent clinical milestones in complement drug discovery, providing an updated translational perspective that may guide optimal target selection and disease-tailored complement intervention

The renaissance of complement therapeutics

The increasing number of clinical conditions that involve a pathological contribution from the complement system - many of which affect the kidneys - has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials

Isothermal Recombinase Polymerase Amplification (RPA) of E. coli gDNA in Commercially Fabricated PCB-Based Microfluidic Platforms

Printed circuit board (PCB) technology has been recently proposed as a convenient platform for seamlessly integrating electronics and microfluidics in the same substrate, thus facilitating the introduction of integrated and low-cost microfluidic devices to the market, thanks to the inherent upscaling potential of the PCB industry. Herein, a microfluidic chip, encompassing on PCB both a meandering microchannel and microheaters to accommodate recombinase polymerase amplification (RPA), is designed and commercially fabricated for the first time on PCB. The developed microchip is validated for RPA-based amplification of two E. coli target genes compared to a conventional thermocycler. The RPA performance of the PCB microchip was found to be well-comparable to that of a thermocycler yet with a remarkably lower power consumption (0.6 W). This microchip is intended for seamless integration with biosensors in the same PCB substrate for the development of a point-of-care (POC) molecular diagnostics platform

Isothermal Recombinase Polymerase Amplification (RPA) of <i>E. coli</i> gDNA in Commercially Fabricated PCB-Based Microfluidic Platforms

Printed circuit board (PCB) technology has been recently proposed as a convenient platform for seamlessly integrating electronics and microfluidics in the same substrate, thus facilitating the introduction of integrated and low-cost microfluidic devices to the market, thanks to the inherent upscaling potential of the PCB industry. Herein, a microfluidic chip, encompassing on PCB both a meandering microchannel and microheaters to accommodate recombinase polymerase amplification (RPA), is designed and commercially fabricated for the first time on PCB. The developed microchip is validated for RPA-based amplification of two E. coli target genes compared to a conventional thermocycler. The RPA performance of the PCB microchip was found to be well-comparable to that of a thermocycler yet with a remarkably lower power consumption (0.6 W). This microchip is intended for seamless integration with biosensors in the same PCB substrate for the development of a point-of-care (POC) molecular diagnostics platform