2015年1月9日讯 /生物谷BIOON/ --自从染色体在生命中所起的重要作用被发现以来，科学家们都一直梦想能够通过直接编辑基因进而从根本上治疗疾病。这个想法乍一听起来似乎没有什么难度，但是如果告诉你在人类基因组中找到一个特定基因位点的难度不亚于从一本长达230万页的大部头书中找到一个特定的排版错误，你是否还会这么认为？事实上这也是科学家们实现基因编辑治疗疾病的最大问题之一。
近年来，一种命名为CRISOR的技术为生命科学家们长期以来的梦想展现了一丝曙光。简单的说，CRISOR就像是一把分子剪刀，它通过特定的RNA回文序列识别特定的基因序列，从而实现靶向剪切编辑DNA。这一现象最早在细菌中被发现，细菌利用类似的系统破坏侵入的病毒DNA，从而杀灭这些噬菌体。
诺华公司最近联手Intellia公司开始探索这一技术在临床上的应用。技术人员介绍，通过这种技术，科学家在体外对患者体内的细胞进行修饰，然后再将其回输至患者体内以达到治疗特定癌症和一些血液病。目前研究人员利用这种技术治疗婴幼儿急性成淋巴细胞性白血病患者并起到了良好的效果，而且在治疗成人慢性淋巴细胞白血病中也有光明的前景。
最重要的是，诺华公司通过引入这一技术将能够进一步深化公司现有的嵌合抗原受体疗法，而后者在2014年成为了世界各大生物医药巨头竞相开发的明星疗法。不过，作为一种新型疗法，人们最关注的还是其安全问题，因此下一步，诺华公司将着重研究这种技术的安全性问题，可以想见，一旦这一疗法变为现实，势必带来医药产业的一次大地震！（生物谷Bioon.com）
详细英文报道：
Imagine trying to find and correct a single typo in a novel that's 2.3 million pages long-more than 3,000 times the length of Moby Dick-without computer software. Scientists face an equivalent task when editing the human genome, which contains approximately 3 billion pairs of DNA "letters." An emerging tool called CRISPR makes the job easier. And it's inspiring researchers to pursue new therapeutic programs.
Think of CRISPR as a pair of molecular scissors that's capable of snipping DNA. The tiny shears are combined with an RNA-based targeting molecule that scans the genome for specific sequences and makes a controlled cut at a single site. Novartis recently entered a collaboration with Intellia Therapeutics, a startup biotechnology company, to sharpen this powerful tool for patients.
"We're planning to modify human cells outside the body and then put them back into patients to treat a number of diseases, beginning with certain cancers and hematologic disorders," says Craig Mickanin, who leads a technology-based group at the Novartis Institutes for BioMedical Research (NIBR) within the Developmental & Molecular Pathways department. "We'll be at the forefront of using CRISPR for clinical validation of gene editing."
The team is exploring how CRISPR can enhance a program that Novartis runs in collaboration with the University of Pennsylvania to reengineer T cells and unleash them on cancer in patients. These chimeric antigen receptor (CAR) T cells-ninjas by design-recognize a marker that's unique to the surface of cancer cells and launch an attack.
In early phase clinical trials, the investigational treatment is proving most effective in pediatric patients with acute lymphoblastic leukemia (ALL), generating complete remissions in 36 of 39 children with the relapsed/refractory form of the disease as of late 2014. It's also showing promise in many adults with chronic lymphocytic leukemia (CLL), although the response rate isn't as high. Perhaps the T cells could be modified further to improve efficacy in adults-and to extend the treatment beyond blood cancers to solid tumors.
"There are a number of challenges that we face with the CART program going forward, and we view gene editing as one of the possible solutions," says Phil Gotwals, who leads a CART group at NIBR that collaborates closely with colleagues in the company's Cell & Gene Therapy Unit.
CRISPR also holds potential for the treatment of certain hematological disorders, where defective blood cells can be removed, edited and then returned to patients.
The Rise of CRISPR
CRISPR isn't the only gene editing system, but it's the newest and offers several apparent advantages.
Targeting molecular scissors to specific sites in DNA is hard, and each editing system has a different way of doing so. With CRISPR, the targeting is accomplished through an RNA template that matches the DNA to be cut.
"The key advantage of the CRISPR-Cas9 system is that it relies on RNA to recognize specific DNA sequences and direct the cutting machinery," explains Mickanin. "We can quickly and easily design RNA guide sequences. Then the cutting is done with Cas9, a protein."
Bacteria use a CRISPR-like system to kill invading viruses. In fact, that is where it was discovered. Jennifer Doudna at the University of California, Berkeley was the first to modify the system for use in eukaryotic cells. Labs around the world, including in NIBR, subsequently have used CRISPR-Cas9 to engineer cell lines and animal models. Therapeutic applications are the logical next step.
"The goal is to build and test multiple therapeutic candidates and then rapidly translate our research into potential treatments for patients."
Safety is top of mind for the Novartis/Intellia team members, so the team will start with ex vivo editing outside the body, which allows for more control. After human cells are modified, the researchers can run them through a battery of tests to ensure that they meet stringent requirements before administering them to patients. If all goes well, in vivo editing might be on the horizon.