title: 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.
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA. Electronic address: tgrossman@isisph.com.
authors: Tamar R
authors: TR
authors: Grossman
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Lisa A
authors: LA
authors: Hettrick
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Robert B
authors: RB
authors: Johnson
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Gene
authors: G
authors: Hung
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Raechel
authors: R
authors: Peralta
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Andrew
authors: A
authors: Watt
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Scott P
authors: SP
authors: Henry
authors: GSK Ophthalmology, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
authors: Peter
authors: P
authors: Adamson
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Brett P
authors: BP
authors: Monia
authors: Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, USA.
authors: Michael L
authors: ML
authors: McCaleb
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D008181:Lupus Nephritis / Q000276:immunology / Q000628:therapy*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D011507:Proteinuria
chemical_list: D000936:Antigen-Antibody Complex; D003176:Complement C3; D016376:Oligonucleotides, Antisense; D011415:Complement Factor B
keywords: Antisense oligonucleotides; Complement; Complement factor B; Lupus nephritis; Therapeutics