Journal
MOLECULAR THERAPY
Volume 30, Issue 10, Pages 3257-3269Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2022.06.018
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Funding
- Veteran's Health Affairs, Washington, DC [1I01BX000357]
- NIH/NEI, Bethesda, MD [5R01EY017294, 5R01EY030774, 1U01EY031650]
- Ruth Kraeuchi Missouri Endowed Chair Ophthal-mology Fund, University of Missouri, Columbia, MO
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This study evaluated the potential of AAV5-mediated Id3 gene therapy to treat corneal scarring. The results showed that AAV5-Id3 gene therapy significantly inhibited corneal fibrosis/haze and reduced the expression levels of related proteins and genes. This anti-fibrotic activity was achieved by reducing the formation of myofibroblasts.
Previously we found that inhibitor of differentiation 3 (Id3) gene, a transcriptional repressor, efficiently inhibits corneal keratocyte differentiation to myofibroblasts in vitro. This study evaluated the potential of adeno-associated virus 5 (AAV5)mediated Id3 gene therapy to treat corneal scarring using an established rabbit in vivo disease model. Corneal scarring/ fibrosis in rabbit eyes was induced by alkali trauma, and 24 h thereafter corneas were administered with either balanced salt solution AAV5-naked vector, or AAV5-Id3 vector (n = 6/group) via an optimized reported method. Therapeutic effects of AAV5-Id3 gene therapy on corneal pathology and ocular health were evaluated with clinical, histological, and molecular techniques. Localized AAV5-Id3 gene therapy significantly inhibited corneal fibrosis/haze clinically from 2.7 to 0.7 on the Fantes scale in live animals (AAV5-naked versus AAV5-Id3; p < 0.001). Furthermore, AAV5-Id3 treatment significantly reduced profibrotic gene mRNA levels: a-smooth fold; p < 0.001), collagen I (0.8-fold; p < 0.001), and collagen III (1.4-fold; p < 0.001), as well as protein levels of a-SMA (23.8%; p < 0.001) and collagens (1.8-fold; p < 0.001). The anti-fibrotic activity of AAV5-Id3 is attributed to reduced myofibroblast formation by disrupting the binding of E-box proteins to the promoter of a-SMA, a transforming growth factor-b signaling downstream target gene. In conclusion, these cellular toxicity in the rabbit eyes.
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