Efficacy of Targeted Complement Inhibition in Experimental C3 Glomerulopathy

Ruseva, Marieta M.; Peng, Tao; Lasaro, Melissa A.; Bouchard, Keith; Liu-Chen, Susan; Sun, Fei; Yu, Zhao-Xue; Marozsan, Andre J.; Wang, Yi; Pickering, Matthew C.

doi:10.1681/asn.2014121195

Cited by 27 publications

(32 citation statements)

References 42 publications

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“…Complement FH abnormalities play a central role in the development of aHUS and DDD. Based on studies in mouse models, full‐length FH and protein constructs with FH fragments have been proposed as treatments for these conditions . However, only scarce information on the distribution of exogenous FH in mice is available.…”

Section: Discussionmentioning

confidence: 99%

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Distribution of exogenous complement factor H in mice in vivo

et al. 2018

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Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self-surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full-length mFH, mFH1-5 and mFH18-20 fragments were radiolabelled, and their distribution was examined in WT, FH and FH C3 mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full-length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1-5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18-20 to kidneys was slower, and at tissue level, mFH18-20 was localized at the proximal tubuli in WT and FH C3 mice. No C3-independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.

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Section: Discussionmentioning

confidence: 99%

“…Based on studies in mouse models, full-length FH and protein constructs with FH fragments have been proposed as treatments for these conditions. 24,32,33 However, only scarce information on the distribution of exogenous FH in mice is available. We investigated the in vivo distribution of exogenous mFH in mice.…”

Section: Discussionmentioning

confidence: 99%

Distribution of exogenous complement factor H in mice in vivo

et al. 2018

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“…There are recombinant proteins that can delivers the complement regulatory region of factor H to tissue-bound C3d. 43, 44 On the other hand, agents that target complement proteins in solution have also been developed. 45, 46 Our results do not exclude a role for fluid phase AP activation in glomerular injury, but they suggest that therapeutic complement inhibitors that are targeted to anatomic sites of complement inhibition will be protective in C3G.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury

Laskowski

Renner

Quintrec

et al. 2016

Kidney International

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Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any one location.

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“…Recently, new therapies have been suggested to target complement pathways owing to an improvement in the understanding of the pathogenesis of C3GN. An anticom plement effect for C3G has been predicted via the use of an animal model 18) . C3G complement blockade eculizumab is a monoclonal antibody targeted against complement C5 that inhibits the activation of the alternative complement pathway.…”

Section: Discussionmentioning

confidence: 99%

“…C3G complement blockade eculizumab is a monoclonal antibody targeted against complement C5 that inhibits the activation of the alternative complement pathway. Although reported results to date are conflicting, many studies have reported an efficacy of eculizumab in patients with C3G, even in children 18,19) . Eculizumab is ap proved by the United States Food and Drug Administration for the treatment of aHUS, thrombotic microangiopathy, and paroxysmal nocturnal hemoglobinuria.…”

Section: Discussionmentioning

confidence: 99%