Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model
Abstract Mutations in the extracellular matrix gene Fibrillin-2 (FBN2) are related to genetic macular degenerative disorders including age-related macular degeneration (AMD) and early-onset macular degeneration (EOMD). It was reported that the retinal protein expression of FBN2 was reduced in patien...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-33886-6 |
| _version_ | 1797560116563673088 |
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| author | Rui Xue Zhang Ying Wen Da Dong Guo Fu Ru Xu Gui Min Wang Xing Rong Wang Yong Wei Shi Jie Ding Qian Jiang Wen Jun Jiang Jost B. Jonas Hong Sheng Bi |
| author_facet | Rui Xue Zhang Ying Wen Da Dong Guo Fu Ru Xu Gui Min Wang Xing Rong Wang Yong Wei Shi Jie Ding Qian Jiang Wen Jun Jiang Jost B. Jonas Hong Sheng Bi |
| author_sort | Rui Xue Zhang |
| collection | DOAJ |
| description | Abstract Mutations in the extracellular matrix gene Fibrillin-2 (FBN2) are related to genetic macular degenerative disorders including age-related macular degeneration (AMD) and early-onset macular degeneration (EOMD). It was reported that the retinal protein expression of FBN2 was reduced in patients with AMD and EOMD. The effect of exogenously supplied fbn2 recombinant protein on fbn2-deficiency-related retinopathy was not known. Here we investigated the efficacy and molecular mechanism of intravitreally applied fibrin-2 recombinant protein in mice with fbn2-deficient retinopathy. The experimental study included groups (all n = 9) of adult C57BL/6J male mice which underwent no intervention, intravitreal injection of adeno-associated virus (AAV) empty vector or intravitreal injection of AAV-sh-fbn2 (adeno-associated virus for expressing short hairpin RNA for fibrillin-2) followed by three intravitreal injections of fbn2 recombinant protein, given in intervals of 8 days in doses of 0.30 μg, 0.75 μg, 1.50 μg, and 3.00 μg, respectively. Eyes with intravitreally applied AAV-sh-fbn2 as compared to eyes with injection of AAV-empty vector or developed an exudative retinopathy with involvement of the deep retinal layers, reduction in axial length and reduction in ERG amplitudes. After additional and repeated application of fbn2 recombinant protein, the retinopathy improved with an increase in retinal thickness and ERG amplitude, the mRNA and protein expression of transforming growth factor-beta (TGF-β1) and TGF-β binding protein (LTBP-1) increased, and axial length elongated, with the difference most marked for the dose of 0.75 μg of fbn2 recombinant protein. The observations suggest that intravitreally applied fbn2 recombinant protein reversed the retinopathy caused by an fbn2 knockdown. |
| first_indexed | 2024-03-10T17:55:57Z |
| format | Article |
| id | doaj.art-6a01a2a44ce644219fc7aaef33efe0e2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-10T17:55:57Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6a01a2a44ce644219fc7aaef33efe0e22023-11-20T09:12:22ZengNature PortfolioScientific Reports2045-23222023-04-0113111310.1038/s41598-023-33886-6Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse modelRui Xue Zhang0Ying Wen1Da Dong Guo2Fu Ru Xu3Gui Min Wang4Xing Rong Wang5Yong Wei Shi6Jie Ding7Qian Jiang8Wen Jun Jiang9Jost B. Jonas10Hong Sheng Bi11Shandong University of Traditional Chinese MedicineAffiliated Eye Hospital of Shandong University of Traditional Chinese MedicineShandong Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of Ocular Diseases, Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of Ocular Diseases in Universities of Shandong, Shandong Academy of Eye Disease Prevention and TherapyAffiliated Eye Hospital of Shandong University of Traditional Chinese MedicineAffiliated Eye Hospital of Shandong University of Traditional Chinese MedicineAffiliated Eye Hospital of Shandong University of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineAffiliated Eye Hospital of Shandong University of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineDepartment of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University HeidelbergAffiliated Eye Hospital of Shandong University of Traditional Chinese MedicineAbstract Mutations in the extracellular matrix gene Fibrillin-2 (FBN2) are related to genetic macular degenerative disorders including age-related macular degeneration (AMD) and early-onset macular degeneration (EOMD). It was reported that the retinal protein expression of FBN2 was reduced in patients with AMD and EOMD. The effect of exogenously supplied fbn2 recombinant protein on fbn2-deficiency-related retinopathy was not known. Here we investigated the efficacy and molecular mechanism of intravitreally applied fibrin-2 recombinant protein in mice with fbn2-deficient retinopathy. The experimental study included groups (all n = 9) of adult C57BL/6J male mice which underwent no intervention, intravitreal injection of adeno-associated virus (AAV) empty vector or intravitreal injection of AAV-sh-fbn2 (adeno-associated virus for expressing short hairpin RNA for fibrillin-2) followed by three intravitreal injections of fbn2 recombinant protein, given in intervals of 8 days in doses of 0.30 μg, 0.75 μg, 1.50 μg, and 3.00 μg, respectively. Eyes with intravitreally applied AAV-sh-fbn2 as compared to eyes with injection of AAV-empty vector or developed an exudative retinopathy with involvement of the deep retinal layers, reduction in axial length and reduction in ERG amplitudes. After additional and repeated application of fbn2 recombinant protein, the retinopathy improved with an increase in retinal thickness and ERG amplitude, the mRNA and protein expression of transforming growth factor-beta (TGF-β1) and TGF-β binding protein (LTBP-1) increased, and axial length elongated, with the difference most marked for the dose of 0.75 μg of fbn2 recombinant protein. The observations suggest that intravitreally applied fbn2 recombinant protein reversed the retinopathy caused by an fbn2 knockdown.https://doi.org/10.1038/s41598-023-33886-6 |
| spellingShingle | Rui Xue Zhang Ying Wen Da Dong Guo Fu Ru Xu Gui Min Wang Xing Rong Wang Yong Wei Shi Jie Ding Qian Jiang Wen Jun Jiang Jost B. Jonas Hong Sheng Bi Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model Scientific Reports |
| title | Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model |
| title_full | Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model |
| title_fullStr | Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model |
| title_full_unstemmed | Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model |
| title_short | Intravitreal injection of fibrillin 2 (Fbn2) recombinant protein for therapy of retinopathy in a retina-specific Fbn2 knock-down mouse model |
| title_sort | intravitreal injection of fibrillin 2 fbn2 recombinant protein for therapy of retinopathy in a retina specific fbn2 knock down mouse model |
| url | https://doi.org/10.1038/s41598-023-33886-6 |
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