AAV Gene Augmentation of Truncated Complement Factor H Differentially Rescues Ocular Complement Dysregulation in a Mouse Model.
Invest Ophthalmol Vis Sci
; 64(10): 25, 2023 07 03.
Article
en En
| MEDLINE
| ID: mdl-37471073
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factor H de Complemento
/
Degeneración Macular
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Invest Ophthalmol Vis Sci
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos