Biber, Josef and Jabri, Yassin and Glaenzer, Sarah and Dort, Aaron and Hoffelner, Patricia and Schmidt, Christoph Q. and Bludau, Oliver and Pauly, Diana and Grosche, Antje (2024) Gliosis-dependent expression of complement factor H truncated variants attenuates retinal neurodegeneration following ischemic injury. JOURNAL OF NEUROINFLAMMATION, 21 (1): 56. ISSN , 1742-2094
Full text not available from this repository. (Request a copy)Abstract
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 Muller 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 Muller 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSLATIONAL MINIREVIEW SERIES; MACULAR DEGENERATION; ALTERNATIVE PATHWAY; MULLER CELLS; GLIAL-CELLS; RECOGNITION; ACTIVATION; GLYCOSAMINOGLYCAN; ABNORMALITIES; RESOLUTION; Complement system; Complement factor H (FH); Retinal degeneration; Gene augmentation; Ischemic injury |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Pädiatrische Ophthalmologie, Strabismologie und Ophthalmogenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Jan 2026 08:06 |
| Last Modified: | 16 Jan 2026 08:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/64798 |
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