DIRECT GENE-TRANSFER WITH DNA LIPOSOME COMPLEXES IN MELANOMA - EXPRESSION, BIOLOGIC ACTIVITY, AND LACK OF TOXICITY IN HUMANS
DIRECT GENE-TRANSFER WITH DNA LIPOSOME COMPLEXES IN MELANOMA - EXPRESSION, BIOLOGIC ACTIVITY, AND LACK OF TOXICITY IN HUMANS
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DOI：
10.1073/pnas.90.23.11307
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发表时间：
1993-12-01
影响因子：
11.1
通讯作者：
CHANG, AE
中科院分区：
文献类型：
--
作者：
NABEL, GJ;NABEL, EG;CHANG, AE
直接基因转移提供了引入DNA编码治疗蛋白质来治疗人类疾病的潜力。以前，人类的基因转移是通过细胞介导的离体方法实现的，在这种方法中，来自患者血液或组织的细胞在实验室进行基因修饰，随后返回患者体内。为了确定直接将基因转移到人体内的可行性和安全性，进行了一项临床研究。通过注射dna -脂质体复合物，将编码外源主要组织相容性复合体HLA-B7的基因引入HLA-B7阴性的晚期黑色素瘤患者，以证明基因转移，记录重组基因表达，并确定该疗法的安全性和潜在毒性。5例hla - b7阴性的IV期黑色素瘤患者完成了6个疗程的治疗，无并发症。在注射后3-7天的肿瘤结节活检中检测到质粒DNA，但聚合酶链反应在任何时候都没有在血清中发现质粒DNA。5例患者的肿瘤活检组织均存在重组HLA-B7蛋白，并检测到对HLA-B7和自体肿瘤的免疫反应。所有患者均未检测到DNA抗体。一名患者在两次独立治疗中表现出注射结节的消退，并伴有远处部位的消退。这些研究证明了人类直接基因转移的可行性、安全性和治疗潜力。
Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.