Chang P L
Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Ann N Y Acad Sci. 1997 Dec 31;831:461-73. doi: 10.1111/j.1749-6632.1997.tb52218.x.
Current human gene therapy relies on genetic modification of the patient's own cells. An alternate non-autologous approach is to use universal cell lines engineered to secrete therapeutic products. Protection with immuno-isolation devices would allow the same recombinant cell line to be used for different patients, thus potentially lowering the cost of treatment. The feasibility of this idea has now been demonstrated in vitro and in vivo. Recombinant gene products with potential therapeutic applications (human growth hormone, factor IX, lysosomal enzymes, adenosine deaminase) have been expressed from genetically modified cells after encapsulation with alginate-poly-L-lysine-alginate or hydroxyethyl methacrylate-methyl methacrylate. We have also demonstrated the feasibility of this idea in vivo. After intraperitoneal implantation, genetically modified mouse Ltk- fibroblasts or C2C12 myoblasts encapsulated in alginate-poly-L-lysine-alginate could deliver recombinant gene products (human growth hormone, human factor IX) to the systemic circulation of mice. The clinical efficacy of this novel approach to gene therapy has now been shown in murine models of human diseases. In the Snell dwarf mice deficient in growth hormone production, implantation of encapsulated mouse myoblasts engineered to secrete mouse growth hormone resulted in increases in body weight, length and organ sizes, some to > 25% above those of the controls. In the Gus/Gus mice suffering from the lysosomal storage disease mucopolysaccharidosis type VII due to deficient beta-glucuronidase, implantation of encapsulated mouse fibroblasts engineered to secrete mouse beta-glucuronidase resulted in delivery of normal levels of the enzyme in the plasma and significant correction of the organ histopathology. Hence, delivery of recombinant gene products through bioartificial devices appears to be a promising strategy for the treatment of genetic diseases.
当前的人类基因治疗依赖于对患者自身细胞进行基因改造。一种替代的非自体方法是使用经过工程改造以分泌治疗性产品的通用细胞系。使用免疫隔离装置进行保护将使同一重组细胞系可用于不同患者，从而有可能降低治疗成本。这一想法的可行性现已在体外和体内得到证实。具有潜在治疗应用的重组基因产物（人生长激素、因子IX、溶酶体酶、腺苷脱氨酶）在用藻酸盐-聚-L-赖氨酸-藻酸盐或甲基丙烯酸羟乙酯-甲基丙烯酸甲酯封装后，已从基因改造细胞中表达出来。我们也已在体内证实了这一想法的可行性。腹腔内植入后，封装在藻酸盐-聚-L-赖氨酸-藻酸盐中的基因改造小鼠Ltk-成纤维细胞或C2C12成肌细胞能够将重组基因产物（人生长激素、人因子IX）递送至小鼠的体循环。这种新型基因治疗方法的临床疗效现已在人类疾病的小鼠模型中得到证实。在生长激素分泌不足的斯内尔侏儒小鼠中，植入经工程改造以分泌小鼠生长激素的封装小鼠成肌细胞导致体重、体长和器官大小增加，有些增加幅度超过对照组的25%。在由于β-葡萄糖醛酸酶缺乏而患有溶酶体贮积病粘多糖贮积症VII型的Gus/Gus小鼠中，植入经工程改造以分泌小鼠β-葡萄糖醛酸酶的封装小鼠成纤维细胞导致血浆中该酶水平正常，并显著纠正了器官组织病理学。因此，通过生物人工装置递送重组基因产物似乎是治疗遗传疾病的一种有前景的策略。
