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Satoshi Kawasaki, Koji Kitazawa, Katsuhiko Shinomiya, Mina Nakatsukasa, Motokazu Tsujikawa, Akira Matsuda, Akira Murakami, Kohji Nishida, Shigeru Kinoshita; Theoretical assessment for the gene therapy of gelatinous drop-like corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2201.
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Gelatinous drop-like corneal dystrophy (GDLD) is caused by the biallelic loss of function mutation of the TACSTD2 gene. There is currently no good fundamental therapy for this disease and it is assumed that gene therapy would be ideal for this disease. In this study, we performed a theoretical assessment for this issue using an immortalized corneal epithelial cells from a GDLD patient.
Immortalized corneal epithelial cells were established from a GDLD (p.Gln118X) patient (iHCE_GDLD cells) as well as from a conjunctivochalasis (wild type TACSTD2) patient (iHCE_normal cells) (I). Lentiviral vector harboring the wild type TACSTD2 gene was infected to the immortalized corneal epithelial cells from a GDLD patient. Change in the expression level and the subcellular localization of tight-junction-related proteins (ZO-1, claudin 1, 4 and 7, and occuludin) as well as epithelial barrier function was assessed before and after the infection. Epithelial barrier function was also assessed. for the mixture of the iHCE_GDLD cells and the iHCE_normal cells with various ratio in order to clarify the requisite gene introduction efficiency for the treatment of GDLD.
Prominent decrease in the expression level as well as the apparent change in the subcellular localization of the claudin 1 and 7 proteins was observed in the iHCE_GDLD cells compared to the iHCE_normal. After the infection of the lentiviral vector harboring the wild type TACSTD2 gene, these pathological differences were almost completely normalized. However, epithelial barrier function was not normalized after the infection, just showing a faint improvement. From the epithelial barrier function experiment using a mixture of the iHCE_GDLD cells and the iHCE_normal cells, it was clarified that 95% gene introduction efficiency was needed for 90% improvement and 80% gene introduction efficiency was needed for 50% improvement in the epithelial barrier function.
Gene therapy is really an efficient treatment for GDLD, but the requisite gene introduction efficiency is quite high for the achievement of clinically-sufficient treatment level.
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