Raper S E, Wilson J M
Department of Surgery, University of Michigan Medical School, Ann Arbor 48109.
Cell Transplant. 1993 Sep-Oct;2(5):381-400; discussion 407-10. doi: 10.1177/096368979300200504.
Somatic cell gene therapy is a new field of biomedical research that encompasses a variety of traditional basic research and clinical disciplines. This new approach to therapeutics has the potential to prevent, treat, or cure a variety of inherited and acquired diseases. Two divergent strategies of hepatocyte transplantation are being employed in animal models and clinical trials in an attempt to correct genetic deficiencies. Allogeneic hepatocyte transplantation has two main advantages over autologous cell transplantation. First, invasive surgical procedures are not required in the recipient. Second, allogeneic cells can be administered repetitively, so that multiple harvests are not necessary. The major drawbacks to allogeneic hepatocyte transplants are rejection and the risks of immunosuppression. Although there is no clinical experience with the treatment of genetic disease by allogeneic hepatocyte transplantation, a variety of animal models have been characterized, including the Gunn rat (UDP-glucuronosyl transferase deficient), the Nagase analbuminemic rat, and the Watanabe heritable hyperlipidemic rabbit (LDL receptor deficient). The use of genetically corrected autologous cells represents a different and more elegant approach to the correction of inherited disease. A segment of liver is harvested from the affected individual. Recombinant retroviruses are used to transduce normal genes--with a variety of promoter/enhancer constructs--into the patients own hepatocytes. The genetically corrected hepatocytes are then transplanted back into the patient. This approach, known as ex vivo gene therapy, eliminates the risk of rejection and the need for immunosuppression. The safety and efficacy of this approach has been proven in a variety of preclinical animals models, including Watanabe rabbits, dogs, and Papio spp. A clinical trial for the treatment of familial hypercholesterolemia is currently in progress. A number of approaches for the reintroduction of hepatocytes into the recipient have been proposed, including catheter-mediated delivery into the inferior mesenteric vein, the umbilical vein, or into the spleen. Candidate diseases, which are likely to result in the first clinical trials include familial hypercholesterolemia, ornithine transcarbamylase deficiency, Crigler-Najjar syndrome, alpha 1-antitrypsin deficiency, and phenylketonuria.
体细胞基因治疗是生物医学研究的一个新领域，涵盖了各种传统基础研究和临床学科。这种新的治疗方法有潜力预防、治疗或治愈各种遗传性和后天性疾病。在动物模型和临床试验中，正在采用两种不同的肝细胞移植策略来纠正基因缺陷。同种异体肝细胞移植相对于自体细胞移植有两个主要优点。第一，受体无需进行侵入性外科手术。第二，同种异体细胞可以重复给药，因此无需多次采集。同种异体肝细胞移植的主要缺点是排斥反应和免疫抑制风险。虽然同种异体肝细胞移植治疗遗传病尚无临床经验，但已经建立了多种动物模型，包括冈恩大鼠（尿苷二磷酸葡萄糖醛酸基转移酶缺乏）、长谷无白蛋白血症大鼠和渡边遗传性高脂血症兔（低密度脂蛋白受体缺乏）。使用基因校正的自体细胞代表了一种不同且更巧妙的纠正遗传病的方法。从患病个体采集一段肝脏。使用重组逆转录病毒将带有各种启动子/增强子构建体的正常基因转导到患者自身的肝细胞中。然后将基因校正的肝细胞移植回患者体内。这种方法称为离体基因治疗，消除了排斥反应风险和免疫抑制的必要性。这种方法的安全性和有效性已在多种临床前动物模型中得到证实，包括渡边兔、狗和狒狒属动物。目前正在进行一项治疗家族性高胆固醇血症的临床试验。已经提出了多种将肝细胞重新引入受体的方法，包括通过导管介导将其输送到肠系膜下静脉、脐静脉或脾脏。可能导致首批临床试验的候选疾病包括家族性高胆固醇血症、鸟氨酸转氨甲酰酶缺乏症、克里格勒 - 纳贾尔综合征、α1 - 抗胰蛋白酶缺乏症和苯丙酮尿症。
