Since most C3 inhibitors, including pegcetacoplan, only recognize human or nonhuman primate C3, testing and evaluating these inhibitors in vivo before a clinical trial are difficult and costly.Ĭas9 was used to induce a double-strand chromosome break near the rat C3 initiation codon. However, this C3 inhibitor is not optimal, and new C3-targeting reagents with better pharmacokinetics and stronger potency are desired. This same C3 inhibitor was also recently approved for treating dry AMD, demonstrating its potential in treating complement-mediated diseases. It effectively prevented both extra- and intravascular hemolysis and significantly reduced the requirement for blood transfusions in the treated patients. Indeed, a small, PEGylated peptide (pegcetacoplan) that directly binds to C3 to inhibit its activation by C3 convertases has been developed and approved for treating patients with PNH. Moreover, C3 is the central component of all complement activation pathways, making it an attractive therapeutic target. Targeting C3 inhibits the activations of both C3 and the downstream C5, which concurrently prevents both extra- and intravascular hemolysis. Ĭomplement component 3 (C3) is upstream of C5 in the complement activation cascade. Consequently, despite the potent inhibition of MAC formation and prevention of intravascular hemolysis by the C5 inhibitors, many PNH patients with the treatment still need frequent blood transfusions to manage their anemia. Besides these MAC-mediated effects, upstream complement activation products C3b/iC3b-mediated extravascular hemolysis is another major pathological mechanism in PNH patients, and C5 inhibitors have no effect on this pathogenic process. In the case of PNH, MAC formation on patient red blood cells leads to intravascular hemolysis and sequential complications. Complement component 5 (C5) inhibitors have been developed and are successfully used to treat several complement-mediated diseases as they potently inhibit the assembly of membrane attack complexes (MACs, C5b-9) that directly form “holes” on the cell surface to cause damage. However, excessive complement activation damages self-tissues, leading to many pathological conditions, such as paroxysmal nocturnal hemoglobinuria (PNH) and age-related macular degeneration (AMD). Its activation not only directly clears invading pathogens but also bridges innate and adaptive immune responses. The complement system is a key effector arm of innate immunity. Conclusion: The successfully developed C3 humanized rats provided a much-desired rodent model to evaluate novel C3 inhibitors in vivo as potential drugs. More importantly, complement-mediated hemolysis in the C3 humanized rats was also inhibited by compstatin both in vitro and in vivo. The newly developed C3 humanized rats appeared healthy and expressed human but not rat C3 without detectable spontaneous C3 activation. Results: We found that supplementing human C3 protein into the C3-deficient rat blood restored its complement activity, which was inhibited by rat factor H or compstatin, suggesting that human C3 is compatible to the rat complement system. We thoroughly characterized the resultant human C3 humanized rats and tested the treatment efficacy of an established primate-specific C3 inhibitor in a model of complement-mediated hemolysis in the C3 humanized rats. Methods: We first studied the compatibility of human C3 in the rat complement system, then developed a C3 humanized rat using the CRISPR/Cas9 technology. However, most, if not all, C3 inhibitors are human or nonhuman primate C3-specific, making evaluating their efficacies in vivo before a clinical trial extremely difficult and costly. Many C3-targeted agents are under extensive development with one already approved for clinical use. Introduction: C3 is central for all complement activation pathways, thus making it an attractive therapeutic target.
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