Gliosis-dependent expression of complement factor H truncated variants attenuates retinal neurodegeneration following ischemic injury.
Complement factor H (FH)
Complement system
Gene augmentation
Ischemic injury
Retinal degeneration
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
22 Feb 2024
22 Feb 2024
Historique:
received:
11
10
2023
accepted:
14
02
2024
medline:
23
2
2024
pubmed:
23
2
2024
entrez:
22
2
2024
Statut:
epublish
Résumé
Inherited, age-related, and acute retinal diseases are often exacerbated by an aberrant or excessive activity of the complement system. Consequently, cells not directly affected by an acute event or genetic variants may degenerate, resulting in enhanced visual impairment. The therapeutic potential of supplementation of complement factor H (FH), a key regulator of the complement cascade, is therefore particularly promising in the context of retinal diseases caused by complement activation. In this study, we engineered adeno-associated viruses (AAVs) containing sequences of two truncated human FH variants. The expression of these variants was regulated by the glial fibrillary acidic protein (GFAP) promoter, which is selectively active in gliotic Müller cells. Both FH variants consisted of FH domains 19-20, which were connected to domains 1-4 and 1-7, respectively, by a polyglycine linker. These AAVs were intravitreally injected following ischemic injury of C57BL/6J mouse retinas. We observed transgene expression in gliotic Müller cells and to some extent in astrocytes. The expression correlated directly with damage severity. Interventions resulted in decreased complement activation, accelerated normalization of microglia activity and morphological improvements. Reduced levels of C3 transcripts and C3d protein in conjunction with higher transcript levels of inhibitory regulators like Cfi and Cfh, hinted at attenuated complement activity. This study demonstrates the great potential of complement regulatory gene addition therapy. With further in vivo testing it could be applied to treat a wide range of retinal diseases where no causative therapies are available.
Identifiants
pubmed: 38388518
doi: 10.1186/s12974-024-03045-3
pii: 10.1186/s12974-024-03045-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
56Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : 399392938 -PA1844/3-1
Organisme : Deutsche Forschungsgemeinschaft
ID : 399392938 - GR4403/5-1
Informations de copyright
© 2024. The Author(s).
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