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Science 3 August 2007:
Vol. 317. no. 5838, p. 580
The death last week of a patient receiving experimental gene therapy for arthritis has triggered a federal review of all trials using the same vector. Few details have been made public; if it turns out that the therapy is to blame, it would be another blow to the field's image. Within 8 years, one patient has died as a result of gene therapy and three have acquired leukemia. This would be the first fatality in a trial not studying a life-threatening disease.
The trial's sponsor, Targeted Genetics Corp. in Seattle, Washington, emphasizes that the company doesn't yet know what caused the patient's death. But it would be a surprise if it were the viral vector, says Chief Scientific Officer Barrie Carter, given that the vector has proved safe in hundreds of patients. He and others are watching nervously for the results of an investigation by the company and the U.S. Food and Drug Administration (FDA). Carter believes it could take weeks. \"I just hope it doesn't put a mark on the entire field,\" says molecular orthopedist Christopher Evans of Harvard Medical School in Boston, who is also planning a test of gene therapy to treat arthritis.
The Targeted Genetics trial builds on the success of a drug called Enbrel, a protein-based treatment for rheumatoid arthritis that inhibits a pro-inflammatory cytokine called tumor necrosis factor alpha (TNF-alpha). Although Enbrel and similar drugs are effective, they don't always penetrate all joints, and they have to be injected regularly. Targeted Genetics uses a modified virus, called an adeno-associated virus (AAV), to shuttle a gene for the TNF-alpha inhibitory protein directly into joints. The joint cells then produce the protein, giving patients \"a localized depot\" of Enbrel that should work long-term, says Carter.
In rats, this strategy \"was pretty impressive\" at reducing inflammation and inhibiting bone destruction, says Sharon Wahl of the National Institutes of Health (NIH) in Bethesda, Maryland, who co-authored the study with Targeted Genetics. Nonhuman primate data also indicated that the approach was safe. In 2003, NIH's Recombinant DNA Advisory Committee (RAC) approved a safety study in humans. Based on those results, FDA approved a multidose study that began in fall 2005 at about 20 sites around the country.
The trial had enrolled 127 patients (32 on placebo) without any serious side effects, says Carter. Seventy-four had received a second dose. But on 20 July, one patient developed a severe adverse event that \"was related in time\" to a second injection, FDA says. The agency put the trial on hold; 4 days later, the patient died. FDA is reviewing the 28 other trials using AAV, including 21 active studies.
Figure 1 Joint effort. A Targeted Genetics vector (tgAAC94) is injected into arthritic joints; cells then make a protein (TNFR:Fc) that blocks the cytokine TNF-alpha.
CREDITS: TARGETED GENETICS; (DESIGN) WOODARD AND CO.
The tragedy has stirred speculation about the cause. One suspect is the gene product, because Enbrel, which suppresses one immune response, has been linked to sepsis and bacterial infections, suggests gene therapy expert Terry Flotte, dean of the University of Massachusetts Medical School in Worcester. But Carter says the protein is \"not necessarily the issue\" because the protein has not been detected in serum from nonhuman primates or patients.
It seems equally unlikely that the problem could be the AAV vector, says Carter. He notes that more than 500 patients have safely received AAV since 1992. However, one difference is that patients in the arthritis trial, unlike the earlier ones, received more than one dose. That raises the possibility that the patient became sensitized to the vector, leading to an adverse reaction, suggests Evans. It happened once before, in 2004, when AAV caused a mild immune reaction in two patients who received the drug in the liver (Science, 4 June 2004, p. 1423).
Gene therapy has restored the health of about 20 children with severe combined immunodeficiency disease. The approach is showing promise against cancer, too, experts note. \"The field is extremely robust,\" says Arthur Nienhuis of St. Jude Children's Research Hospital in Memphis, Tennessee, and president of the American Society of Gene Therapy. Meanwhile, Carter says his company is \"working furiously\" to figure out what caused the death before RAC meets to consider the case in mid-September.
《科学杂志》8月3日报道--------上周一名关节炎患者在一项基因治疗的临床试验中死亡，由此引发了全国上下对所有使用该基因治疗载体（腺相关病毒AAV）所进行的临床试验的重新审查。关于此事件几乎没有消息透露给公众；如果责任最终归咎于治疗方法本身，那将会是对整个基因治疗领域的动摇。在过去8年内的基因治疗试验中，1名患者死亡，3名在治疗过程中患上白血病。上周的事件将会是第一个在非致命性疾病的临床研究中发生死亡的事件。
该临床试验的发起者是位于华盛顿州西雅图的Targeted Genetics公司，公司首席科学官Barrie Carter说，患者的死因现尚未可知，但如果死因是病毒载体引起的，那将令人吃惊，因为此前成百上千的患者都证明AAV是安全的。Targeted Genetics公司目前所有人都紧张地关注着FDA对此事的调查结果。Carter认为调查将会持续几周，同样正在计划一项关节炎基因治疗临床试验的哈弗医学院分子骨科医生Christopher Evans说，“我希望这件事不要连累到整个基因治疗领域”。
Targeted Genetics的临床试验建立在一种叫Enbrel的蛋白药物的基础上，此药用于治疗类风湿性关节炎，原理是其可以抑制TNF-alpha的作用。尽管Enbre及类似药物颇有疗效，但它们不总是能对所有关节都有效，并且需要长期按时注射。Carter说，Targeted Genetics利用基因重组改造过的AAV来携带TNF-alpha基因直接进入关节，随后关节细胞合成TNF-alpha蛋白，在关节处形成一个“局部的Enbrel仓库”，以使TNF-alpha能够长期起作用。
该研究项目的合作者NIH的Sharon Wahl说，在大鼠实验中，这一方案对于减轻发炎和抑制骨破坏的效果“令人印象深刻”。非人类灵长动物的试验结果也显示了其安全性。2003年NIH的DNA重组顾问委员会批准了该项目在人体上的安全性实验。根据以上实验结果，FDA批准了始于2005年秋在全国20多个地方开展的的多剂量临床研究。
该临床试验征集了127名患者（其中32名接受安慰剂治疗），没有一例出现严重的副作用，之后74名患者接收了第二剂给药。据FDA称，7月20日一名患者在接收第二剂给药后即出现了严重不良反应。此后实验暂停，4天后该名患者死亡。FDA重新审查了其他28项使用AAV为载体的临床试验，其中包括21项正在进行中的试验。
图1. 共同作用. Targeted Genetics公司的tgAAC94载体注射到关节部位后，细胞合成可抑制TNF-alpha作用的TNFR:Fc蛋白。
CREDITS: TARGETED GENETICS; (DESIGN) WOODARD AND CO.
这起事故引起了对患者死因的猜测。基因治疗专家马萨诸塞大学医学院主任Terry Flotte猜测，该基因产物TNFR:Fc蛋白抑制了免疫反应，与败血症和细菌感染有关。但Carter说， TNFR:Fc蛋白不一定是罪魁祸首，因为不论在非人类灵长动物还是在人体实验中，血清里都没有检测到TNFR:Fc蛋白。同样AAV也不太可能是凶手，因为自从1992年起，500多名患者安全地接受了AAV治疗。Evans说，不同于以往的是在该实验中，患者接受了不只一剂的载体注射，这可能增加了患者对载体的敏感度，导致不良反应的发生。在2004年也发生过一次同样的事件，2名患者在肝部注射AAV后发生了轻度免疫反应(Science, 4 June 2004, p. 1423)。
专家指出，基因治疗已经治愈了大约20名患有联合免疫缺陷症的儿童，并且在治疗癌症方面也显示出很好的前景。美国基因治疗社区主席，田纳西州St. Jude儿童研究医院的Arthur Nienhuis说“这一领域发展极为迅速”。 Targeted Genetics公司现在正在“疯狂地工作”，以期在九月中旬DNA重组顾问委员会会议讨论此事之前找出死亡事件的原因。 |
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发表于 2007-9-13 13:34:36