Gene Therapy without Viruses

A new, highly effective polymer may make gene therapy safer

The promise of gene therapy has long been held up by the lack of a safe and effective way to insert the desired therapeutic genes into the right cells. To solve that problem, MIT researchers have developed a new polymer for gene therapy that is as effective as viruses, the standard carriers, but it seems to have none of the risks of viral treatments. The researchers have successfully tested a version of the polymer in mice with ovarian cancer, and they believe they can further modify the polymer to target virtually any cell in the body.

Gene therapy works by delivering to a specific group of diseased cells copies of a gene that corrects what ails them. "If you could get it [a gene] where it's needed, you could treat many diseases," says the MIT Center for Cancer Research's Daniel Anderson, one of the leaders of the polymer research group.

The most effective way to get therapeutic genes to the right cells in the body has been by inserting them into viruses, which are then injected into patients. But a series of high-profile setbacks has raised questions about the safety of using viral vectors. Injections of these viruses have caused dangerous, and in several cases deadly, immune reactions in some patients. And one class of viruses used for gene therapy can cause leukemia. There are currently many viral gene therapies in clinical trials, but none have been approved by the Food and Drug Administration.

These problems in clinical trials using viruses have spurred researchers to search for synthetic alternatives for delivering gene therapy. "Polymers have been shown safe in people for years," says Robert Langer, a professor of chemical engineering at MIT and a pioneer in biomaterials research. The polymers under development by the MIT group are relatively inexpensive to manufacture and break down into harmless byproducts in the body. The kind of polymer used as a starting material by the MIT researchers naturally associates with DNA and can succeed in delivering genes into cells.

"They have something comparable [in effectiveness] to viruses," says David Putnam, assistant professor of chemical and biomolecular engineering at Cornell University. "No one has been able to achieve this."

The MIT researchers succeeded because they have developed rapid systems for developing and testing large numbers of polymers, says Putnam. "A lot of materials development is a numbers game," he explains, and the MIT group can design and test new polymers "an order of magnitude faster than everybody else."

The MIT researchers have previously used an unmodified version of the polymer to selectively deliver a suicide gene to prostate tumors in mice. For their current research, published last week in Advanced Materials, they experimented with making small chemical changes to the ends of the polymers.

基因疗法无病毒

一个新的，高效的聚合物可使基因疗法更安全

分子生物学在过去半个世纪的发展，对人类健康和医学发展产生了质的推动。其成果之一是带动过去十几年医学分子生物学的成长，已经形成一门新的学科分子医学。基因疗法就是其中一个令人兴奋的领域。它广阔的应用前景让世人为之期待。但是由于缺乏安全和有效的插入目标治疗基因的方法，使基因疗法发展步伐受到很大影响。目前基因疗法大都使用无毒性的流感病毒作为载体，把治疗疾病的基因通过转基因操作植入某种细胞中去，然后注射到病灶处，以杀死病菌。这种方法的缺点是很难把治病基因准确地送到病灶处，因此不得不大量注射药物，从而存在着产生副作用的危险。

为了解决这一问题，美国麻省理工学院科学家已研发出一种与病毒载体同样高效的新型聚合物，而且目前看来似乎没有危险病毒载体的毒副作用风险。研究人员已经成功地针对小鼠卵巢癌在小鼠体内测试了一种版本的聚合物，他们相信他们可以进一步改进聚合物可以应用到几乎任何体内细胞。

原来最有效的基因治疗途径，是将治疗基因插入到一个病毒载体中，然后将此病毒载体再注入病人体内。而一系列问题已经对使用病毒载体的安全性提出质疑。注射这些病毒载体可能使一些病人发生严重的免疫反应。也曾经有患者接受基因治疗导致白血病的报道。目前有许多病毒载体基因疗法的临床试验，但没有一个能够通过美国食品和药物管理局(Food and Drug Administration)的批准。

这些问题促使科学家致力于寻找基因治疗中病毒载体的替代品。 "多年来已被证明聚合物对人体是安全的，"生物材料研究先驱，麻省理工学院（MIT）化学工程教授Robert Langer说。MIT研究小组发明的这种聚合物造价相对低廉，而且能在体内分解成无害的产物。MIT研究人员用的这种聚合物能够自然的与DNA结合，然后成功把目的基因运送到细胞内。

“它们与病毒载体相比更加有效”，康乃尔大学化学与生物工程系助理教授David Putnam说， "目前没有其他东西能够达到这一点" 。

麻省理工学院的研究员成功，是因为他们已经制定了快速开发和测试大量的聚合物的系统，Putnam说。 "许多材料的开发，其实是一种数字游戏"，他解释说，“MIT小组可以设计和测试新型聚合物的量级高于其他所有人" 。