Targeting complement in neurodegeneration: challenges, risks, and strategies

• Published in: Trends in pharmacological sciences (Regular ed.) 2022-08, Vol.43 (8), p.615-628
• Main Authors: Zelek, Wioleta M., Morgan, B. Paul
• Format: Article
• Language: English
• Subjects: blood–brain barrier; complement; drugs; neurodegeneration; neuroinflammation
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2022.02.006

Evidence implicating complement in neuroinflammatory and neurodegenerative diseases (NDDs) has accumulated over the past decade, revealing complement as a driver of pathology across these diverse diseases. Over the same period, there has been an explosion of interest in the development of complement-modulating drugs, first for a few rare complement dysregulation diseases but recently also for more common diseases where complement contributes to the disease process. To date, there has been little attention paid to the potential role of anticomplement drugs in neurodegeneration and the current landscape does not feature drugs that can enter the central nervous system (CNS), a prerequisite in most NDDs. Here we summarise the evidence implicating complement in neurodegeneration, build the case for testing anticomplement drugs, and discuss how drugs may be modified or designed de novo to inhibit complement in neurodegeneration. For most neurodegenerative diseases (NDDs), therapeutic options are limited, providing symptomatic benefit but not impacting disease progression; new treatments addressing critical effectors in the disease process are needed.Evidence implicating complement in NDDs has accumulated over the past two decades, establishing complement dysregulation as a driver of pathology and a novel target for therapy in these diseases.Over the same period, highly effective anticomplement drugs have been developed for therapy of complement dysregulation; however, their use to date has been restricted to rare systemic diseases.Current anticomplement drugs are not fit for purpose in most NDDs because they do not adequately access the central nervous system (CNS).Blood–brain barrier-penetrant anticomplement drugs, created either by modifying current drugs or by designing new drugs, could suppress complement dysregulation, neuroinflammation, and neurodegeneration to halt or slow disease progression.Inhibition of complement is not without risk; this might be particularly the case in the CNS and requires close attention.