ESTABLISHMENT OF A RAT STRATIN WITH MUCOPOLYSUCCHARIDOSIS TYPE VI AS AN ANIMAL MODEL FOR GENE THERAPY

本研究通过对大鼠芳基硫酸酯酶B基因的克隆和测序，比较了该基因的核苷酸序列，发现了一个引起基因移码的插入突变。我们进一步揭示了包括突变的区域的扩增能够容易地鉴定突变的携带者大鼠。我们进行了骨髓移植以确认补充正常酶产生细胞的治疗效果。结果表明，MPR大鼠骨髓移植后，其器官内无糖胺聚糖蓄积，尿中无糖胺聚糖排泄，面部畸形和骨性骨折部分消退，提示骨髓移植对人粘多糖病VI型有治疗作用，是一种理想的动物模型。

The present research project was carried out to establish the MPR rat as an animal model for human hereditary mucopolysuccharidosis type VI by identifying the mutation responsible for the phenotypes and by examinating therapeutic effects of bone marrow transplantation.We compaired the nucleotide sequences of the rat arylsulfatase B gene by cloning nad sequencing the gene, and found an insertional mutation that causes a fram-shift of the gene. We further revealed that an amplification of the region including the mutation enables to easily identify carriar rats of the mutation.We performed bone marrow transplantation to confirm therapeutic effects of supplement of the normal enzyme producing cells. The recipient rats showed no accumulation of glycosaminoglycan in organs and no urinary excretion of the glycosaminoglycan but partial resoluation of facial dysmorphia and bony feutures, indicating therapeutic effects of the bone marrow transplantation.We, therefore, concluded that the MPR rat is a useful animal model for mucopolysaccharidosis type VI of human.