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深圳赛百诺:基因治疗

级别: 管理员
Gene Machine Sibiono GeneTech Uses Gene Therapy to Treat Cancer

This year's winner occupies a sensitive area of health: gene therapy. Gene therapy, put simply, is when genes -- the instruction manual for how everything in an organism operates -- are manipulated to alter the way a cell -- the components of the organism -- works. It's called therapy because it has been developed to tackle disorders arising from human genes that have mutated or are defective.

This is a sensitive area for several reasons: gene therapy is as controversial as any area of study involving our genetic material. And the death of a patient in the U.S. in 1999 has cast a long cloud over researchers and investors. Which is partly why the first company to commercialize gene therapy for cancer is based in China: Shenzhen-based SiBiono GeneTech Co.

Gene therapy works like this: Genes contain the information necessary for cells to function and multiply. This genetic information is contained in DNA, long thin strands built from combinations of four sorts of bases.

When cells multiply by splitting, these combinations are passed on and checked by genes called regulators for errors, so that new cells are identical to the old cells.

But the process can sometimes go wrong, creating mutant cells. Or sometimes we are born with defective genes. Either way, gene therapy's approach is to replace the bad gene with a good one.

It sounds simple enough, but it's not. The first problem is to identify the healing, or therapeutic gene. Then, a way has to be found to deliver the corrected gene to the target cells, because a gene, unlike chemicals, cannot spontaneously enter cells.

This is usually done, perhaps illogically, by giving the patient a virus. A virus, it turns out, is a very good delivery system for this kind of thing since it's good at getting inside cells and then duplicating (the virus is modified so it is not pathogenic, or disease causing, and won't replicate once inside host cells.)

Once the gene is in the cell, it still has a long way to go. First it must find its way into the inner sanctum of the cell, the nucleus. From there it must be activated so that it can start issuing its payload to the cell.

In the case of cancer, gene therapy largely focuses on one small gene -- p53, so called because its expressed protein has a molecular weight of 53,000 daltons (a dalton is roughly the weight of a hydrogen atom).

The p53 gene is a very special, very complex gene, since it appears to act as a kind of guardian to the genome, or central directory of genes. The p53 is still only partially understood, but one thing is clear: it's intimately connected to at least half of all human cancers.

A group of special proteins constantly patrol the genome looking for faults in the DNA; if they find one they immediately report to the p53 gene, which in turn is released in packs of four to sort out the problem.

"DNA damage," David Lane, who discovered p53 in 1979, wrote in the New Scientist, "makes the genome unstable and prone to mutation and disintegration."

The problem is that DNA is constantly being multiplied as cells divide, so the damage needs to be resolved quickly before it spreads.

This is what p53 genes do, putting a halt on cell growth until repairs are done. If the cell is beyond repair, the p53 gene forces the cell to self-destruct, something called apoptosis.

But what happens if the p53 isn't working properly? This is what happens in many cancer cases. If the p53 gene is faulty, or has been bent out of shape by a virus, the patrolling proteins may report back on faults in the DNA chain, but the p53 gene does not function correctly.

In this case there is nothing to stop the cancerous cells from multiplying, and tumors to grow. "For a healthy person cells just divide regularly, via a regulator gene like p53," says Dr. Chiushi Fu, assistant to the founder and CEO of SiBiono, Dr. Zhaohui Peng. "But with a cancer patient the regulatory cell loses control so the cells divide without limit."

The secret, then, in combating cancer with gene therapy is to somehow ensure the p53 does its job. The most obvious way is to introduce "good" p53 genes into tumor cells, which is exactly what SiBiono GeneTech does by building a payload of a "healthy" p53 gene packed into a viral delivery mechanism called an adenoviral vector, containing a class of virus that would normally cause respiratory, intestinal and eye infections (including the common cold).

Once inside the nucleus the particles will unload their healthy p53 genes which, it is hoped, will then begin to do the job they're supposed to do -- halting the spread of cancerous cells.

SiBiono, under Dr. Peng, saw cancer as a natural focus for gene therapy. Unlike surgery, chemotherapy or radiotherapy, gene therapy went to the heart of the problem by tackling the genetic abnormality that causes the cancer in the first place.

The Gendicine therapy, the company's submission for the award says, "treats cancer from the very root of its initiation and development." That's not to say gene therapy can't be conducted in tandem with other therapies.

Indeed, SiBiono says that trials have thrown up some unexpected but positive findings in patients, including improved appetite, relief of cancerous pain and resistance to the side effects caused by radiotherapy or chemotherapy.

SiBiono has also been fortunate, if that's the right word, to step into a void left by setbacks in Europe and the U.S.

In 1999 an 18-year-old American man died from multiple organ failure four days after joining a gene-therapy trial, apparently reacting to the adenovirus carrier. And U.S. authorities in 2003 placed a temporary halt on some gene-therapy trials using a different viral-delivery mechanism after a French child developed leukemia-like conditions after gene therapy.

China, on the other hand, has been supportive of work in this field, including government investment from ministries and the local municipal government.

The company denies that processes are more lax, pointing out that China's regulatory body issued gene-therapy guidelines in 2003. Clinical costs are also lower in China, a fraction of the tens of thousands of dollars a U.S. company would have to pay per person.

Gendicine was approved by China's regulatory body in October 2003 and was officially launched six months later, the world's first commercially available gene-therapy product.

More than 4,000 patients from 26 countries have received treatment, without any reports of severe side effects, according to the company. SiBiono says sales of Gendicine reached 11.4 million renminbi ($1.4 million) in 2004 and it projects sales this year of nearly 19 million renminbi.

But that's not to say it has been a simple process to get this far. In the early years "it was a very difficult road," says Dr. Fu. "We put a lot of money in and at that time there was still risk."

Western competitors had more money, and trying to recruit patients in China was not easy. "We had to tell them what it is, they had no idea -- including the doctors," Dr. Fu recalls.

In the end, says Dr. Fu, the continued success of Gendicine will depend on whether it continues its initial promise. "The efficacy of the drug is the bottom line," he says. "Or I should call it the lifeline?" y
深圳赛百诺:基因治疗

今年的获奖者来自基因治疗这一敏感的医学领域。所谓基因治疗,简言之就是通过操纵基因来改变细胞的行为方式。基因是各种生命现象的幕后导演,而一切生物体都是由细胞构成的。之所以被称做“治疗”,那是因为这种技术可以消除因人体基因发生变异或出现缺陷而导致的人体病变。

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这一医学领域之所以敏感的原因有如下几个:基因治疗与涉及人体遗传材料的任何研究领域一样都充满争议。而美国一位接受基因治疗的病人1999年不治身亡一事则给基因治疗技术的研究者和投资者长期蒙上了心理阴影。这可以部分解释为什么第一个在以基因技术治疗癌症方面实现了商业化的公司出现在中国。这家公司就是总部位于深圳的赛百诺基因技术有限公司(SiBiono GeneTech Co.)。

基因治疗的原理是:基因包含了使细胞得以发挥功能并实现复制的必要信息。这些遗传信息包含在DNA这种由四种基本物质所形成的化合物构建的细长链条中。

当细胞通过分裂方式进行复制时,这些构成DNA的化合物被从旧细胞传递到新细胞,而基因则负责审核这些化合物在传递过程中不出现走样,以便新复制的细胞能与旧细胞一模一样。

但这一审核过程有时也会出错,从而导致细胞发生变异。 而有的人天生就有基因缺陷。不管出现哪种情况,都可以通过基因治疗用正确的基因替换出错的基因。

这事听起来简单,但实际却很复杂。首先需要找到能够起治疗作用的基因,然后需找到将这一修复后的基因送入目标细胞的方法。与化学物质不同,基因不能自行进入细胞。

人们通常用给病人注入病毒的方法来做到这一点,这或许听起来不合逻辑。病毒是将基因送入细胞的一种十分理想的载体,因为它很擅长于钻入细胞然后在里面复制自身(用作载体的病毒都经过改造,一方面被消除了毒性,同时也丧失了在细胞中自我复制的能力。)

使基因进入细胞只是漫漫征途迈出的第一步。首先必须使基因进入细胞核。然后这一基因在细胞核中必须被激活,这样它才能扮演细胞复制监督官的角色。

就针对癌症的基因治疗而言,p53这一小型基因往往成为人们重点关注的对象,由于其表达蛋白的分子量为53,000道尔顿(1道尔顿的重量大约相当于一个氢原子),故有此名。

p53基因非常特别且复杂,因为它似乎扮演着基因组(基因中心目录)守护者的角色。虽然人们对p53的了解还不充分,但有一点是明确的:它与人类至少一半的癌症都密切相关。

人体中有一组特殊的蛋白质会经常对照基因组来检查DNA是否出现了错误;一旦发现错误,它们会立即通报p53基因,后者则会四个一组地前去找出这一错误。

问题是DNA常常会随着细胞的分裂而成倍增多,因此必须赶在有缺陷的DNA被大量复制前及时修复它。

这正是p53基因要做的工作,它会暂停细胞的增长直到修复工作完成。如果有缺陷细胞已无法修复,那么p53基因会强迫这一细胞自我毁灭。

但如果p53基因无法正常工作会发生什么情况?许多癌症正是由此而生的。如果p53本身出了错,或者因病毒侵袭而失去了功效,那么当负责巡视的蛋白质将DNA链上的错误报告给它时,p53基因就无法正确发挥作用了。

如果发生癌变的细胞能够不受阻止地不断自我复制,就会形成肿瘤。赛百诺基因技术有限公司的创办人兼首席执行长彭朝晖的一位助手说:“在p53这类基因的监督下,健康的人体细胞只会有规律地分裂,但如果这一监督机制失效,细胞就会无限制地分裂,这时人就会生癌。”

那么,通过基因治疗来治疗癌症的关键就是确保p53基因正常工作。这方面最显而易见的做法就是将“良好的”p53基因注入肿瘤细胞,赛百诺的做法就是借助所谓腺病毒载体(包含一系列通常会引发呼吸道、肠道和眼部感染的病毒)将“健康的”p53基因批量注入肿瘤细胞。

一旦进入肿瘤细胞的细胞核,健康的p53基因将像人们预想的那样发挥作用──终止肿瘤细胞的扩散。

彭朝晖领导的赛百诺公司自然而然地将基因疗法的重点放在治疗癌症上。与手术、化疗和放疗不同,基因治疗直指癌症的要害,赶在第一时间消除引发癌症的遗传变异。

赛百诺公司称其参与此次评奖的基因药物“今又生”是从源头上治疗癌症。这并不是说基因治疗不能与其他疗法配合使用。

赛百诺称,临床试验表明基因治疗已在癌症病人身上取得了一些出乎意料的积极效果,如食欲增强、疼痛减轻以及抗放、化疗副作用的能力提高等。

而欧洲和美国在基因治疗方面所走的弯路使赛百诺在这一领域所面临的竞争大为减少。

1999年,美国一位18岁的男子在参加一个基因治疗的临床试验4天后因身体多个器官出现衰竭而死亡,显然他的身体是对充当基因载体的腺病毒产生了不良反应。此后又发生过一起一名法国男孩在接受基因治疗后出现类白血病症状的事例,美国政府遂于2003暂停了用另一种病毒传送机制进行的基因治疗试验。

而中国对在本国进行基因治疗试验一直持支持态度,政府有关部门以及地方政府都向这一领域投入了资金。

赛百诺公司否认中国政府对基因治疗试验持放任态度,它指出中国的监管部门2003年就发布了有关基因治疗的指导原则。中国的临床试验成本也比较低,美国公司这方面的费用折合到每个参与试验的病人身上高达数万美元,比中国的临床试验成本高出许多。

“今又生”于2003年10月通过了中国监管部门的审查,并于6个月后正式上市销售,它是全球首个投入商业销售的基因治疗药物。

赛百诺公司称,目前已有26个国家的4,000多位病人接受了这一药物的治疗,尚未发现病人有严重的副作用产生。该公司称“今又生”2004年的销售额为人民币1,140万元(合140万美元),预计今年的销售额将接近人民币1,900万元。

但赛百诺公司取得今天的成绩可不是一帆风顺的。上述那位彭朝晖的助手说,公司当初曾冒着风险在这一项目上投入了大量资金。

他回忆说,当初招募参加临床试验的病人就不是一件容易事,那些人对基因治疗一无所知,赛百诺不得不向他们详加解释。

他说,“今又生”能否继续取得成功归根结底将取决于它的疗效。

Jeremy Wagstaff
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