Dolan, Katie, Liao, Sha-Mei, Crowley, Maura, Xiang, Chuanxi, Adams, Christopher, Brown, Ann, Vo, Nhi, Chen, Amy, Delgado, Omar, Buchanan, Natasha, Guo, Chenying and Prasanna, Ganesh (2024) Complement factor B inhibition or deletion is not sufficient to prevent neurodegeneration in a murine model of glaucoma. Journal of ocular pharmacology and therapeutics. ISSN https://doi.org/10.1089/jop.2024.0046

Abstract

Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification of common complement pathways in glaucoma is not well understood. We evaluated complement factor B expression in post-mortem human ocular tissues with or without glaucoma, and the effect of FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM).
Methods: Human CFB mRNA in postmortem human eyes was assessed by RNAscope and TaqMan. The HAGM model was performed on C57BL6/J mice. The effect of FB in the HAGM model was evaluated with an oral FB small molecule inhibitor and Cfb-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and Western blot, respectively.
Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days post IOP induction in WT mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent RGC or axon loss 30 days post IOP induction in mice.
Conclusion: The essential alternative complement component FB may not substantially contribute to RGC loss in glaucoma in the mouse model of ocular hypertension despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.

Item Type:	Article
Keywords:	Complement, FB, mouse, glaucoma, neuroprotection, Pharmacokinetics/Pharmacodynamics (PK/PD)
Date Deposited:	05 Oct 2024 00:45
Last Modified:	05 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53022