Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

Abstract

The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain

“…Activation of these receptors produces a variety of effects, including increase in vascular permeability, chemotaxis, production and release of inflammatory factors, and stimulation of phagocytosis. C3aR-and C5aR1-mediated effects are particularly prominent in various pain states, including postsurgical pain, neuropathic pain, CRPS and arthritis (Figure 1) (15,40,(48)(49)(50)(51)(52). To limit systemic activation, both C3a and C5a are rapidly "des-arginated" by serum carboxypeptidases.…”

“…These improved pharmacokinetic characteristics J o u r n a l P r e -p r o o f combined with promising preclinical data in animal models of AD, ALS and spinal cord injury, make PMX205 a promising candidate for future therapeutic development. Many additional drug candidates that target C5a/C5aR1 signaling and other components of the complement system are currently at various stages of clinical trials for a variety of chronic pathological conditions (30,31,52). A more nuanced understanding of specific complement-mediated mechanisms that drive neurological symptoms and of disease-specific temporal aspects of complement system activity, is expected to identify windows of opportunity as well as novel targets for the treatment of a wide range of neuropathological conditions for which efficacious clinical approaches have been lacking.…”

“…C3aR- and C5aR1-mediated effects are particularly prominent in various pain states, including postsurgical pain, neuropathic pain, CRPS, and arthritis ( Fig. 1 ) ( 8 , 14 , 36 , 44 , 45 , 46 , 47 ). To limit systemic activation, both C3a and C5a are rapidly “des-arginated” by serum carboxypeptidases.…”

“…Overcoming the described limitations will be essential for success in therapeutic targeting of the complement system for treating chronic pain and other neuropathological conditions. Despite the many remaining unanswered questions about the complement system and the complexities inherent to targeting its components for therapeutic purposes, there are already clinically utilized tools targeting the complement system such as cinryze, eculizumab, ravulizumab, and pegcetacoplan ( 26 , 27 , 47 , 180 ). Cinryze is a human plasma-derived C1-INH inhibitor that is indicated for treating hereditary angioedema (HAE), a genetic disease characterized by episodic attacks of swelling of extremities, face, and gastrointestinal tract, with the latter causing severe abdominal pain ( 181 ).…”

“…Several recently developed small-molecule inhibitors of C5aR1 have also shown promise in preclinical and clinical studies for various conditions ( 26 , 27 , 47 ). Selective targeting of C5aR1 without concomitant inhibition of the TPCC/MAC complex is expected to provide a better safety profile for these drugs than that for eculizumab or ravulizumab, particularly where chronic dosing of elderly individuals is required.…”