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

本课题拟通过对MPR大鼠进行表型突变鉴定和骨髓移植治疗效果检测，建立MPR大鼠作为人类遗传性黏液多糖苷病VI型的动物模型。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，发现了一个导致该基因移框的插入突变。我们进一步发现，对包含突变的区域进行扩增，可以很容易地识别突变的携带大鼠。我们进行了骨髓移植，以证实补充正常产酶细胞的治疗效果。接受骨髓移植的大鼠器官内无糖胺聚糖蓄积，尿中无糖胺聚糖排泄，但面部畸形和骨骼特征得到部分缓解，提示骨髓移植的治疗作用。因此，我们认为MPR大鼠是人类粘多糖病VI型的一个有用的动物模型。

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.