Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice

Abstract

Systemic lupus erythematosus is an autoimmune disease that manifests in widespread complement activation and deposition of complement fragments in the kidney. The complement pathway is believed to play a significant role in the pathogenesis and in the development of lupus nephritis. Complement factor B is an important activator of the alternative complement pathway and increasing evidence supports reducing factor B as a potential novel therapy to lupus nephritis. Here we investigated whether pharmacological reduction of factor B expression using antisense oligonucleotides could be an effective approach for the treatment of lupus nephritis. We identified potent and well tolerated factor B antisense oligonucleotides that resulted in significant reductions in hepatic and plasma factor B levels when administered to normal mice. To test the effects of factor B antisense oligonucleotides on lupus nephritis, we used two different mouse models, NZB/W F1 and MRL/lpr mice, that exhibit lupus nephritis like renal pathology. Antisense oligonucleotides mediated reductions in circulating factor B levels were associated with significant improvements in renal pathology, reduced glomerular C3 deposition and proteinuria, and improved survival. These data support the strategy of using factor B antisense oligonucleotides for treatment of lupus nephritis in humans.

Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome

“…Compounds that target CFB already exist, and taken together with the findings in our study, suggest that CFB has significant potential as a novel target for treatment of metabolic disease 39 , 40 …”

Persistent Breeding-Induced Endometritis in Mares—A Multifaceted Challenge: From Clinical Aspects to Immunopathogenesis and Pathobiology

“…Complement is an important contributor to opsonization activity in uterine secretions and inflammatory cell chemotaxis, preceding an inflammatory response [114]. In the classical complement pathway, the C4 subunit binds to IgM/IgG-associated C1q, initiating the enzymatic cleavages of C4 into C4a and C4b and C2 into C2a and C2b [115] (Figure 1). The association of C4b with C2b activates C3 convertase.…”

New milestones ahead in complement-targeted therapy

“…This latest example illustrates an increasingly explored therapeutic option that involves interference with complement on the genetic level and is slowly finding its way into complement-targeted treatment. In addition to ALN-CC5 by Alnylam and the above-mentioned C6-suppressing locked-nucleic acid (LNA) program by Regenesance, Ionis has shown initial preclinical data for antisense oligonucleotides against FB and FD [59, 60]. The primary target for these approaches is the expression of complement proteins by the liver, and such genetic antisense approaches may provide a comprehensive inhibition of systemic secretion.…”