[The pathogenesis and treatment of corneal disorders].
In this 21 st century, it is predicted that blindness caused by corneal disorders which are difficult to prevent or treat will increase. It is important to study the pathogenesis, prevention, and treatment of these corneal disorders. Two corneal disorders, keratoconus and corneal dystrophy, were investigated to elucidate the pathogenesis by using molecular biological or molecular genetic techniques. Corneal transplantation is performed to restore vision of patients with corneal disorders, but the condition of the donor corneal endothelium is the key to maintaining transparency of the grafted cornea. We investigated the function or cell cycle mechanism of corneal endothelium at the level of the gene, and we also studied induced genes of endothelial cells during preservation of donor corneas. 1. Keratoconus: We searched for keratoconus patients with questionnaires sent to 141 hospitals in the 23 Wards of Tokyo. The incidence of patients was estimated to be 12.4 x 10(-5) for males and 6.7 x 10(-5) for females. The male/female ratio was 1.7: 1.0. The number of male patients was low when compared with studies reported 17 years ago. Rupture of Descemet's membrane in males was significantly higher than in females. Genesis of incidence: Apoptosis-related gene expression in thinning of the cornea was analyzed with cDNA microarrays, using mRNA isolated from cultured keratocytes of normal human corneas and keratoconus corneas. The expression of tumor necrosis factor alpha-induced protein 6(TNFAIP 6) was more enhanced, while insulin growth factor binding protein 5(IGFBP 5) was less expressed in keratoconus patients. 2. Corneal dystrophy: In corneal dystrophy related to four candidate genes such as transforming growth factor beta-induced(TGFBI) gene, membrane component 1 surface maker 1(M 1 S 1) gene, carbohydrate sulfotransferase gene 6(CHST 6), and collagen type VIII alpha-2(COL8 A 2) gene, 208 Japanese and 42 Vietnamese families were analyzed for the gene mutation and studied for the frequency of gene mutation and differences of clinical features. About 80% of Japanese with corneal dystrophies had mutation of the TGFBI gene and about 70% of them had Avellino corneal dystrophy. However, in Vietnamese patients, mutations were found in both the TGFBI gene (lattice corneal dystrophy; the phenotype gene was His 626 Arg) and in the CHST gene. The difference in frequency in gene mutations was significant between the two nationalities. Moreover, a novel corneal dystrophy associated with Asp 123 His mutation in TGFBI gene was found in one Vietnamese family. 3. Corneal endothelial cell: 1) gene expression: We performed random sequence and homology research analysis of 1,000 clones from a rabbit corneal endothelial cDNA library. Forty-five genes, including collagen type VIII alpha-1, were listed for the frequently observed cDNA in the library. 2) gene transfection: One of the causes of a growth-arrested state in human corneal endothelium was thought to be the presence of transforming growth factor-beta (TGF-beta) in aqueous humor. The transfection of Smad 7 gene, which blocks the signal, showed proliferation of the endothelial cells in the presence of aqueous humor. This suggests that there may be a possible practical application for using gene transfection with a non-viral DNA vector or with an adenovirus vector.
Kanai
Atsushi
A
Department of Ophthalmology, Juntendo University School of Medicine, Tokyo. 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D003316:Corneal Diseases / Q000209:etiology* / Q000628:therapy*; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged