基因治疗影响脏器血供危害不小

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Gene Silencing Therapies Could Have Harmful Side Effects, Research Suggests
ScienceDaily (Mar. 28, 2008) — A dramatic new study published in the most recent issue of Nature questions some of the mechanisms underlying a new class of drugs based on Nobel Prize-winning work designed to fight diseases ranging from macular degeneration to diabetes.
ScienceDaily (3月28日, 2008)—在《自然》杂志上最近发表的一项引人注目的研究，质疑了一些基于一种曾经获得诺贝尔奖的可能设计出治疗黄斑变性和糖尿病等疾病方法的新药的机制问题。
Dr. Jayakrishna Ambati, a University of Kentucky researcher and the paper's senior author, has for years been investigating gene silencing, a 1998 discovery that won a Nobel Prize in Physiology or Medicine in unusually quick fashion in 2006
肯塔基大学的Jayakrishna Ambati医生和本论文第一作者一直致力于基因沉默的研究，1998年发现存在基因沉默的现象，并且在2006年获得诺贝尔生理学和医学奖。
While the prize-winning discovery remains important, the findings made by Ambati's lab show the mechanisms behind it are not as scientists once believed. In fact, Ambati's work imparts the need for caution in current clinical trials using the technology, as it may have potentially harmful effects on subjects.
但是该项获奖研究确实十分重要，Ambati研究所所发现的揭示了其背后机制，其机制并不像科学家一度想象的那样。事实上，Ambati的工作说明了在临床应该慎用基因沉默技术的必要性，因为它可能对受试者有潜在的危害性。
Gene Silencing Leads to New Class of Drugs
基因沉默导致新药开发
In short, researchers in 1998 discovered a class of double-stranded RNA (dsRNA) that possessed powerful gene-silencing capabilities, or the ability to \"turn off\" disease-causing genes in the body.
简言之，研究者在1998年发现了一种极有利导致基因沉默的双链RNA，换言之它可以“关掉”身体内导致疾病的基因。
The technique of targeting these dsRNA for single genes was refined with synthetic molecules called small-interfering RNA (siRNA). siRNA were thought to have the capability to interfere with specific disease-causing genes and prevent them from being expressed.
这种针对单个基因双链RNA技术可精简为一种人工合成的小RNA分子（siRNA）。siRNA具有干扰特定疾病发起基因和防止其表达的能力。
Because gene-targeted silencing with siRNA does not involve permanent DNA mutations, this approach rapidly gained popularity throughout biomedical research. The breakthrough, with the powerful ability to turn off genes, has become a standard research tool for genetic studies and has resulted in a new class of 21st century drugs designed to silence disease-causing genes in the body or disarm an invading virus by knocking out its genes.
因为由siRNA介导的特定基因靶向沉默并不导致永久的DNA突变，这种技术迅速受到生物医学研究领域的青睐。这种突破物质，有很强的关闭基因的能力，已经在基因研究方面成为一种标准研究工具并且使人们发现21世纪的可以沉默疾病基因或者通过关闭病毒基因解除病毒致病能力的新药。
Many diseases including age-related macular degeneration, diabetes, kidney disease, cancer, Lou Gehrig's and Parkinson's have been heralded as candidates for siRNA therapy, creating a wave of on-going clinical trials.
包括与年龄相关的黄斑退行性改变，糖尿病，肾脏病，癌症，肌萎缩侧索硬化和帕金森症等许多疾病被认为是siRNA疗法的潜在适应症，这已经在进行临床试验。
New Discovery Shows Therapies Could Have Harmful Side Effects
新的发现现实这种疗法可能带来有害的副作用
Ambati, professor and vice chair of ophthalmology and visual sciences at the University of Kentucky College of Medicine, and his colleagues have made a critical discovery that challenges the view that siRNA's therapeutic effects are imparted solely through RNA interference.
肯塔基大学医学系的眼科和视觉科学教授Ambati，和他的同事有了一项关键发现，它向siRNA独自在基因沉默发挥作用的观点发出挑战。
Ambati and collaborators argue that siRNA functions generically rather than specifically, thus the new class of drugs being formulated may actually adversely affect blood vessel growth in a variety of organs.
Ambati和其同事讨论了siRNA作用的广泛性，不仅仅是特异性，因此，这种新型药物可能现在会对不同器官的心血管生成不利
\"siRNAs are used in every area of biomedical research and are thought to be exquisitely specific in targeting a single gene,\" Ambati said. \"My lab made the surprising discovery that siRNAs, including those in clinical trials, do not enter cells or trigger RNAi. Rather, we found that they generically, regardless of their sequence or target, bind a receptor known as TLR3 on cell surfaces and block blood vessel growth in the eye, skin and a variety of other organs.\"
“siRNA在生物医学研究的各个领域被应用，并且被看作有寻找单基因的强烈特异性。”Ambati说“我们的研究所有惊人的发现，包括那些临床试验在内的siRNA并不进入细胞或者靶向RNAi。更合适的说，不管他们的结果或者目的，它拮抗了一种被命名为TLR3的细胞表面受体并且阻止了眼睛，皮肤和其他各器官的血管生长”
Blocking blood vessel growth is beneficial in a variety of diseases. Prime examples include wet AMD, an eye disease hallmarked by the abnormal growth of blood vessels beneath the retina, as well as cancer. However, blocking blood vessel growth by administering siRNA intravenously could be detrimental if it impacts other organs, according to Ambati's study.
阻止血管生成对各种疾病都有有利作用。最初实例包括湿性老年黄斑变性，一种视网膜下血管异常增生的眼科疾病，癌症也是如此。但是，根据Ambati的研究表明，如果它影响到其他器官，通过静脉给与siRNA来阻碍血管生成可能造成不良后果。
Ambati, however, quickly notes the Nobel Prize-winning discovery is still valid.
但是Ambati指出其获得诺贝尔奖依然是值得的。
\"RNA interference does, of course, exist,\" said Ambati, a University Research Professor and the Dr. E. Vernon Smith & Eloise C. Smith Endowed Chair in Macular Degeneration Research. \"It is just that siRNA functions differently than commonly believed -- not via RNA interference.\"
“基因沉默，当然存在”一位大学教授Ambati和黄斑变性研究赞助主席E. Vernon Smith和Eloise C. Smith医生说。“这只是siRNA的功能不同于我们通常所想的那样通过基因沉默来发挥作用”
Ambati said the main implications of his research are two fold:

1、for researchers to understand how siRNAs actually work

2、for clinical trials of siRNA to be approached with great caution.
Ambati说他的研究主要含义有两层：
1， 找到siRNA究竟是如何工作的
2， 更谨慎的进行siRNA临床试验
Ambati's lab also showed that people with a mutation in the TLR3 receptor would be resistant to the generic effects of siRNAs, thereby providing hope for personalized medicine in this population.
Ambati的试验室也表明TLR3受体变异的人可能对siRNA的基因效应产生抵抗，因此带来了对这部分人进行个体化治疗的可能性。
The next steps, Ambati said, are to better understand the generic mechanism of siRNA that inhibits blood vessel growth and to discover how to render it useful in creating treatments for the many conditions that would benefit from such effects. His lab also will work to refine siRNAs to potentially achieve their promise of precise gene targeting.
下一步，Ambati说，使更好的了解siRNA阻止血管生长的基因机制和为了发现如何才能利用这种效应得有利功能在治疗上发挥作用。他的研究所也将致力于研究如何更精确的使siRNA完成它的寻找靶向基因作用。

基因疗法确实应该谨慎，因为人体太复杂了，单凭体外的模拟，不可能面面俱到，还是多在猴子上做实验吧，不过可怜的猴子，人真自私，有时在想，人通过吃别的生物活着，其实很残忍的。