锌指蛋白针对单个基因的疾病治疗方法探究

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How zinc-finger proteins treat illness by aiming at a single gene
From The TimesMarch 18, 2008
来源：泰晤士报 2008-3-18

A new way of turning genes on and off, pioneered by a Nobel prize-winning British scientist, is promising to transform treatment of conditions such as HIV/Aids, heart disease and diabetes.
一种新的基因调控方法（激活或者沉默基因）有望改变我们当前针对诸如爱滋病、心脏病以及糖尿病等疾病的治疗方法；该方法最先由一位获得诺贝尔奖的英国科学家提出。

The technique, devised by Sir Aaron Klug, of the Laboratory of Molecular Biology in Cambridge, allows scientists to act with unprecedented precision against genes that affect a wide range of diseases, switching them on or off permanently.
由剑桥大学分子生物学实验室的Aaron Klug先生发明的这项技术允许科学家们针对那些影响许多疾病的基因进行前所未有的精确操作，其中包括永久地激活或者沉默这些基因。

The first drugs designed to target the genes have begun clinical trials in the United States on patients with arterial disease and diabetes-induced nerve damage. A third trial, for HIV, is due to begin within months. If they are successful, scientists predict that the technique could change the way many diseases are treated, making genetic therapies a routine part of medicine for the first time.
基于该技术设计的首批靶向基因的药物已经在美国开始临床试验了，主要是针对具有动脉疾病和由糖尿病引发的神经损伤的病人。第三个临床试验是针对艾滋病（HIV）的，计划在月内开始。科学家们预测，如果上述临床试验成功，该项技术将改变许多疾病的治疗方式，使遗传治疗第一次成为医学的一个常规部分。

In some cases, the method will be used to switch off rogue genes that promote conditions such as heart failure or cancer. In others, it will help to activate genes that protect against nerve damage or encourage blood vessel growth.
在某种情况下，该方法将会用来沉默一些能引发诸如心衰或者癌症的不好的基因。在另一种情况下，人们将用它来激活那些可以保护神经免受损伤或者有助于血管生成的基因。

In treating HIV, the aim is to modify T-cells from patients’ immune systems so that they become immune to infection with the virus. This would leave them with some working T-cells with which to fight off other infections, which are the chief cause of Aids deaths. The technique relies on a natural process by which the activity of genes is raised or lowered by proteins called transcription factors.
在治疗艾滋病时，治疗的手段就是通过对病人免疫系统的T细胞的修饰使其对爱滋病毒免疫。如果成功的话，这将使患者体内具有部分保持正常功能的T细胞，这部分具有正常功能的T细胞就能有效应付由艾滋病引发的其它感染（由艾滋病引发的其它感染往往是患者致死的主要原因），从而挽救患者生命。自然界中有一类名为转录因子的蛋白可调节（升高或者降低）基因的活性，该技术正是基于该机理。

In 1985 Sir Aaron discovered a new class of proteins that mimic this function and can recognise specific stretches of DNA and bind to them, boosting the activity of genes or damping them down.
1985年Aaron先生发现了一类具有与转录因子类似功能的新的蛋白；该蛋白能够识别特定的DNA区域并且结合上去，从而导致基因活性上升或者下降。

He named them zinc-finger proteins, after the metal that holds them together and the way in which they grasp DNA. Sangamo BioSciences, a company in California, has already developed several drugs based on the principle.
他根据该结合该蛋白的金属种类以及该蛋白结合DNA的方式把该类蛋白命名为锌指蛋白。根据该方法，加州的一家名为Sangamo BioSciences的生物公司已经开发出了几种药物。

A zinc-finger protein specific to a gene is loaded with an enzyme called a nuclease, which will bind to the gene and turn it on or off. Sir Aaron told The Times: “We are taking nature’s own method of regulating gene activity and exploiting it for our own purposes. We can use this technique to change the function of a single gene permanently.
锌指蛋白以一种叫做a核酸酶（a nuclease）的酶为载体结合在特定的基因上并将该基因沉默或者激活（不同的锌指蛋白结合的基因不同）。Aaron先生跟泰晤士报说：“我们利用自然界自身调节基因活性的方法，再根据我们的目的加以改进。我们能够利用该项技术永久地改变某个基因的功能”。

“The beauty of zinc-finger nucleases lies in their simplicity. Where other methods are long, arduous and often messy, it is relatively easy to switch off genes using this method. The zinc-finger design allows us to target a single gene, while the nuclease disrupts the gene.”
“锌指核酸酶的美妙之处就在于其简单性，比起其它费时、费力又麻烦的方法来，利用锌指核酸酶的方法能够相对容易地沉默基因。我们可以通过对锌指的设计来靶向单个（特定的）基因，与此同时，核酸酶的存在将破坏该基因。”

Details of the technique are published today in the journal Proceedings of the National Academy of Sciences.http://www.pnas.org/cgi/content/ ... ;resourcetype=HWCIT
有关该技术的详细信息刊登在今天的《美国国家科学院院刊》（Proceedings of the National Academy of Sciences）上。网址是：http://www.pnas.org/cgi/content/ ... ;resourcetype=HWCIT

The most advanced of Sangamo’s drugs uses a zinc-finger nuclease to treat diabetic neuropathy, a common complication of diabetes that causes nerve damage and pain. The drug binds to a gene called VEGF-A, which is known to protect the nervous system, and switches it on to prevent nerve damage. Phase 2 trials of the drug are under way. The same gene is also being targeted to treat peripheral arterial disease which causes blocked arteries in the limbs. A zinc-finger drug that has started safety trials aims to stimulate VEGF-A activity, which can promote the growth of new arteries.
Sangamo公司最新型的药采用一种锌指核酸酶来治疗糖尿病性神经病变，一种常见的由糖尿病引发的神经损害和神经痛。该药物结合在一个名为VEGF-A的具有神经系统保护功能的基因上，接着激活VEGF-A基因，从而达到保护神经系统的目的。目前，关于该药物的2期临床实验正在进行中。VEGF-A基因同样是针对外周动脉疾病的治疗的靶基因，外周动脉疾病是一种能够导致四肢动脉阻滞的疾病。一种锌指药物已经开始安全测试，该测试旨在刺激VEGF-A的活性，从而刺激新的动脉血管的生成。

In the longer term, a similar approach might be used to grow new blood vessels in the heart, Sir Aaron said.
长远看来，某种类似的方法可能被用来在心脏中生成新的血管，Aaron先生称。

Sangamo is applying for regulatory permission to start testing a zinc-finger nuclease on HIV patients as well as developing drugs to treat glioblastoma, a type of brain cancer, and single-gene disorders such as sickle-cell anaemia.
Sangamo公司正在申请在HIV病人身上测试一种锌指核酸酶药物以及开发成胶质细胞瘤（一种脑瘤）和诸如镰状细胞贫血等单基因病的药物的管制许可。