Drugmakers’ Fever for the Power of RNA Interference Has Cooled 主要原因是目前的 给药方式或手段 不给力： "But the biggest challenge has been delivery. RNA is quickly broken down in the bloodstream. And even if it gets to the cells in the body where it is needed, it has trouble entering the cells. "
2009年11月12日 HIV艾滋病毒在受其感染的细胞中复制自己的遗传基因。德国癌症研究中心的科学家首次发现，这些病原体却几乎绝不侵犯人类基因的某些特定地方。这项发现将有可能促进新的、特定的艾滋病药物的研发。 附着在细胞膜上的艾滋病病毒的电镜照片 摄像师：德国癌症研究中心汉斯瓦尔特．岑特格拉夫(Hanswalter Zentgraf)教授 正如所有的逆转录酶病毒，艾滋病病原体HIV病毒会将自己的基因复制到寄主细胞的基因组上。原则上HIV所选择的切入点都是活跃的、会被经常读取的基因。由此给病毒带来的好处是，由于总能在那些地方找到大量负责读取基因的酶，从而可以利用寄主细胞的机能实现复制自身的目的。 在德国癌症研究中心工作的高级讲师斯蒂芬妮．劳夫斯(Stephanie Laufs)博士和弗兰克．佐丹奴(Frank Giordano)博士，就艾滋病毒是否可以做为用于进行基因治疗的基因载体开展了研究。对她们而言，最关键的问题是艾滋病毒可以在宿主细胞的什么位置插入自己的遗传物质。对于基因疗法而言，这是一个非常关键的环节，因为根据插入位置的不同，这个过程或者会永久地激活癌基因或者引发其他损伤。研究人员需要知道确切答案，因而对46,000多个艾滋病毒载体可用的已知的整合位点进行了分析。这些整合位点或者来自于各种不同的基因治疗研究或者来自于基因数据库。 迄今为止，研究人员一直认为艾滋病毒以及艾滋病毒载体尤其偏爱那些开始读取基因的地方。这里可以找到过量的、所有病毒都需要的酶。数据库的分析却给了一个全然不同的结果：尽管许多的HIV病毒确实整合在基因读取点的附近，当研究人员仔细检验时发现，就在最临近艾滋病病毒切入点的地方，换言之在1000个DNA结构单元的“左边”或“右边”，几乎都找不到基因的端点。 “我们因此第一次也是非常准确地找出了人类基因组中那些艾滋病病毒不会或极少切入的位点”，佐丹奴说。科学家们都为此结果而震惊，因为艾滋病毒避讳这些地方必定是有原因的。 “我们推测这里一定是有个特别机制，阻止了病毒的通路”，佐丹奴说并且继续补充道：“反过来当然也可能是这些地方缺少了某个必要的能辅助艾滋病毒切入的因素。”研究人员已然知道，这绝非是一个非特定的道路阻断：“其他反转录病毒甚至会专选读取端点插入自己的遗传基因”，劳夫斯说道。“因此我们可以推断，有某种机制防止了艾滋病毒基因组切入到活跃基因的读取端点，并阻止了艾滋病毒的融合。”这种作用机制有可能抑制所谓的整合过程，这个过程会把病毒DNS安装到细胞基因组中去。 这种酶是目前寻找一种更理想的艾滋病疗法的核心。目前现有的高活性的疗法可以通过不同的药物从各个方面攻击病毒：逆转录酶抑制剂可以阻断病毒遗传物质的复制。蛋白酶抑制剂可以压制新的病毒蛋白发育成熟。作为治疗严重免疫缺陷的理想的办法，是阻断病毒基因组安装到细胞的DNS中。具有如此效果的成份 - 所谓的整合酶抑制剂 – 也才刚刚只用了数年，但是通过突变在某种程度上如今的病毒已经使效果降低。因此，病毒研究人员正在抓紧寻找可以关断病原体的关键酶的新措施。阻止艾滋病毒从读取端点切入的机制，极有可能成为开发这类作用成份的分子学样版。 原始文献：Frank A. Giordano, Jens-Uwe Appelt, Manuela Zucknick, Mohammed Abba, W. Jens Zeller, Stefan Fruehauf, Heike Allgayer and Stephanie Laufs: Cold spots in hot spots: transcription start sites of active genes are spared from HIV vector integration. AIDS 2009, DOI: 10.1097/QAD.0b013e3283336432
http://www.sciencenet.cn/htmlnews/2009/9/223460.shtm 动物实验显示可用基因手段治疗色盲 英国《自然》杂志网站9月16日发布的一项最新研究成果说，雄性松鼠猴由于基因缺陷是天然的红绿色盲，但如果向其眼部细胞注入所缺少的基因，就变得可以识别红色和绿色。这表明将来可用基因手段治疗色盲。 来自美国华盛顿大学等机构的研究人员介绍说，松鼠猴控制识别红色和绿色的基因分别位于两条X染色体上，雄性松鼠猴因为只有一条X染色体，所以就成了天生的红绿色盲。 研究人员培养了能指导合成红色视蛋白的基因，并利用病毒载体将其注入到两只雄性松鼠猴的视网膜。之后进行的色盲测试结果显示，它们辨别颜色的能力大大提高，可以分辨红色和绿色。目前两只松鼠猴已经保持这种能力超过2年，并且没出现明显的副作用。 此前曾有理论认为，如果是先天色盲，那么大脑神经中可能缺少识别新颜色的能力。而这次动物实验显示，只需要在眼睛中加入所缺少的视蛋白基因，神经系统就可以分辨并处理新的颜色。研究人员下一步将进行临床试验。 更多阅读 《自然》相关报道（英文） Published online | Nature | doi:10.1038/news.2009.921 | Nature | doi:10.1038/news.2009.921 News Colour blindness corrected by gene therapy Treated monkeys can now see in technicolour. Elie Dolgin Dalton, a squirrel monkey treated with gene therapy, enjoys his new colour sense. Neitz Laboratory Researchers have used gene therapy to restore colour vision in two adult monkeys that have been unable to distinguish between red and green hues since birth raising the hope of curing colour blindness and other visual disorders in humans. This is a truly amazing study, says Andrs Komromy, a vision researcher and veterinary ophthalmologist at the University of Pennsylvania in Philadelphia, who was not involved in the research. If we can target gene expression specifically to cones then this has a tremendous implication. About 1 in 12 men lack either the red- or the green-sensitive photoreceptor proteins that are normally present in the colour-sensing cells, or cones, of the retina, and so have redgreen colour blindness. A similar condition affects all male squirrel monkeys ( Saimiri sciureus ), which naturally see the world in just two tones. The colour blindness in the monkeys arises because full colour vision requires two versions of the opsin gene, which is carried on the X chromosome. One version codes for a red-detecting photoreceptor, the other for a green-detecting photoreceptor. As male monkeys have only one X chromosome, they carry only one version of the gene and are inevitably redgreen colour blind. A similar deficiency accounts for the most common form of dichromatic color blindness in humans. Fewer female monkeys suffer from the condition as they have two X chromosomes, and often carry both versions of the opsin gene. Here is an animal that is a perfect model for the human condition, says Jay Neitz of the University of Washington in Seattle, a member of the team that carried out the experiment. The monkeys were trained to touch a screen when they saw coloured patches. Neitz Laboratory Neitz and his colleagues introduced the human form of the red-detecting opsin gene into a viral vector, and injected the virus behind the retina of two male squirrel monkeys one named Dalton in honour of the British chemist, John Dalton, who was the first to describe his own colour blindness in 1794, and the other named Sam. The researchers then assessed the monkeys' ability to find coloured patches of dots on a background of grey dots by training them to touch coloured patches on a screen with their heads, and then rewarding them with grape juice. The test is a modified version of the standard 'Cambridge Colour Test' where people must identify numbers or other specific patterns in a field of coloured dots. Colour coded After 20 weeks, the monkeys' colour skills improved dramatically, indicating that Dalton and Sam had acquired the ability to see in three shades (see video ). Both monkeys have retained this skill for more than two years with no apparent side effects, the researchers report in Nature 1 . Adding the missing gene was sufficient to restore full colour vision without further rewiring of the brain even though the monkeys had been colour blind since birth. There is this plasticity still in the brain and it is possible to treat cone defects with gene therapy, says Alexander Smith, a molecular biologist and vision researcher at University College London, who did not contribute to the study. It doesn't seem like new neural connections have to be formed, says Komromy. You can add an additional cone opsin pigment and the neural circuitry and visual pathways can deal with it. ADVERTISEMENT
标签: 基因治疗
