Jin Y Chen, Lingjun Zhang, Maojing Yang, Elizabeth D Hughes, Zachary T Freeman, Thomas L Saunders, Feng Lin
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引用次数: 0
Abstract
Introduction: C3 is central for all complement activation pathways, thus making it an attractive therapeutic target. Many C3-targeted agents are under extensive development with one already approved for clinical use. 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.
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. 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.
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. The newly developed C3 humanized rats appeared healthy and expressed human but not rat C3 without detectable spontaneous C3 activation. More importantly, complement-mediated hemolysis in the C3 humanized rats was also inhibited by compstatin both in vitro and in vivo.
Conclusion: The successfully developed C3 humanized rats provided a much-desired rodent model to evaluate novel C3 inhibitors in vivo as potential drugs.
期刊介绍:
The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.