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http://dx.doi.org/10.25673/115556
Titel: | Gliosis-dependent expression of complement factor H truncated variants attenuates retinal neurodegeneration following ischemic injury |
Autor(en): | Biber, Josef![]() Jabri, Yassin Glänzer, Sarah Dort, Aaron Hoffelner, Patricia Schmidt, Christoph Q. Bludau, Oliver ![]() Pauly, Diana ![]() Grosche, Antje ![]() |
Erscheinungsdatum: | 2024 |
Art: | Artikel |
Sprache: | Englisch |
Zusammenfassung: | 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. |
URI: | https://opendata.uni-halle.de//handle/1981185920/117510 http://dx.doi.org/10.25673/115556 |
Open-Access: | ![]() |
Nutzungslizenz: | ![]() |
Journal Titel: | Journal of neuroinflammation |
Verlag: | BioMed Central |
Verlagsort: | London |
Band: | 21 |
Originalveröffentlichung: | 10.1186/s12974-024-03045-3 |
Seitenanfang: | 1 |
Seitenende: | 21 |
Enthalten in den Sammlungen: | Open Access Publikationen der MLU |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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s12974-024-03045-3.pdf | 13.76 MB | Adobe PDF | ![]() Öffnen/Anzeigen |