Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization
| العنوان: | Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization |
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| المؤلفون: | Elisabeth Obert, Cecile Nasarre, Bärbel Rohrer, Gloriane Schnabolk, Balasubramaniam Annamalai, Stephen Tomlinson, Nathaniel Parsons, Alfred S. Lewin |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 9, Iss, Pp 1-11 (2018) Molecular Therapy. Methods & Clinical Development |
| بيانات النشر: | Elsevier BV, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, lcsh:QH426-470, genetic structures, Complement receptor 2, retinal pigment epithelium, chemical and pharmacologic phenomena, Gene delivery, choroidal neovascularization, Article, 03 medical and health sciences, Genetics, Medicine, lcsh:QH573-671, age-related macular degeneration, Molecular Biology, Retinal pigment epithelium, lcsh:Cytology, business.industry, complement factor H, AAV, Macular degeneration, medicine.disease, eye diseases, 3. Good health, Complement system, lcsh:Genetics, 030104 developmental biology, Choroidal neovascularization, medicine.anatomical_structure, Factor H, Alternative complement pathway, Cancer research, Molecular Medicine, sense organs, medicine.symptom, business |
| الوصف: | Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2-mCherry) using subretinal delivery in C57BL/6J mice. Secretion of CR2-fH was confirmed in polarized retinal pigment epithelium (RPE) cells. A safe concentration of AAV5-VMD2-CR2-fH was identified using electroretinography, optical coherence tomography (OCT), RPE morphology, and antibody profiling. One month after gene delivery, CNV was induced using argon laser photocoagulation. OCT assessment demonstrated reduced CNV with AAV5-VMD2-CR2-fH administration. Bioavailability studies revealed that gene-therapy delivered similar levels of CR2-fH to the RPE/choroid as treatment by intravenous injections, and C3a ELISA verified reduced CNV-associated ocular C3a production. These results contribute to existing data illustrating the importance of the AP of complement in CNV development and its potential role in AMD treatment. Demonstration of AAV-vector efficacy opens new avenues for the development of treatment strategies. Keywords: age-related macular degeneration, choroidal neovascularization, complement factor H, AAV, retinal pigment epithelium |
| تدمد: | 2329-0501 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1359b940954672c2132c23dd77cff65Test https://doi.org/10.1016/j.omtm.2017.11.003Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d1359b940954672c2132c23dd77cff65 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23290501 |
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