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Tamar R Grossman, Robert B Johnson, Lijiang Shen, Lisa A Hettrick, Scott P Henry, Brett P Monia, Michael McCaleb; Reduction in Ocular Complement Factor B Protein in Mice and Monkeys by Systemic Administration of Factor B Antisense Oligonucleotide. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5000.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in many industrialized countries and the complement system plays an important role in the pathogenesis of AMD. Inhibition of complement factor B (FB), a key regulator of the alternative pathway, is implicated as a potential therapeutics for AMD. Here we investigated the effect of liver FB reduction on systemic and ocular FB levels.
Antisense oligonucleotides targeting mouse and monkey FB mRNA were administered by subcutaneous injections to normal mice or monkeys and the level of FB mRNA was assessed in the liver and eye by qRT-PCR. FB protein level was determined in plasma and whole eyes from the treated animals by western blot analysis for ocular and plasma FB protein levels and ELISA for monkey plasma FB protein level.
Mice and monkeys treated with FB ASOs demonstrated a robust reduction in liver FB mRNA level (79±10% and 66±7% of saline control, respectively), with no change in ocular FB mRNA levels. In addition, plasma FB protein level was significantly reduced in mice and monkeys treated with FB ASO (97±0.5% and 80±6% of saline control, respectively), leading to a dramatic reduction in ocular FB protein in mice and monkeys, below the detection level measured by western blot.
The results add to the increasing evidence that the liver is the main source for plasma and ocular FB protein, and demonstrate that reduction of liver FB mRNA by an ASO targeting FB gene results in a significant reduction in plasma and ocular FB protein. Moreover, our results suggest that inhibition of liver FB mRNA by FB ASO would reduce systemic alternative complement pathway activation and has potential to be used as a novel therapy for AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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