AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a Mouse Model.

Autor:	Grigsby D; Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States., Klingeborn M; Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States.; McLaughlin Research Institute, Great Falls, Montana, United States., Kelly U; Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States., Chew LA; Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States.; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States., Asokan A; Departments of Surgery, Molecular Genetics and Microbiology, and Biomedical Engineering, Duke University School of Medicine, Durham, North Carolina, United States., Devlin G; Departments of Surgery, Molecular Genetics and Microbiology, and Biomedical Engineering, Duke University School of Medicine, Durham, North Carolina, United States., Smith S; Applied Genetic Technologies Corporation, Alachua, Florida, United States., Keyes L; Pfizer, Morrisville, North Carolina, United States., Timmers A; Editas Medicine, Cambridge, Massachusetts, United States., Scaria A; Applied Genetic Technologies Corporation, Alachua, Florida, United States., Bowes Rickman C; Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States.; Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States.
Jazyk:	angličtina
Zdroj:	Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2023 Jul 03; Vol. 64 (10), pp. 25.
DOI:	10.1167/iovs.64.10.25
Abstrakt:	Purpose: Complement dysregulation in the eye has been implicated in the pathogenesis of age-related macular degeneration (AMD), and genetic variants of complement factor H (CFH) are strongly associated with AMD risk. We therefore aimed to untangle the role of CFH and its splice variant, factor H-like 1 (FHL-1), in ocular complement regulation derived from local versus circulating sources. We assessed the therapeutic efficacy of adeno-associated viruses (AAVs) expressing human FHL-1 and a truncated version of CFH (tCFH), which retains the functional N- and C-terminal ends of the CFH protein, in restoring the alternative complement pathway in Cfh-/- mouse eyes and plasma. Methods: Using Cfh-/- mice as a model of complement dysregulation, AAV vectors expressing tCFH or FHL-1 were injected subretinally or via tail vein, and the efficacy of the constructs was evaluated. Results: Following subretinal injections, tCFH expression rescued factor B (FB) retention in the eye, but FHL-1 expression did not. By contrast, both constructs restored FB detection in plasma following tail vein injections. Both tCFH and FHL-1 proteins accumulated in the posterior eyecup from the circulation following liver transduction; however, neither was able to significantly regulate local ocular complement. Conclusions: Our findings demonstrate that the C-terminus of human CFH is necessary for complement regulation in the murine eye. Furthermore, exogenous CFH must be synthesized locally to maximize complement regulation in the retina. These findings establish a critical foundation for development of CFH augmentation-based gene therapies for the eye.
Databáze:	MEDLINE
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