生物谷报道：微小RNA (microRNA，简称miRNA)是生物体内源长度约为20－23个核苷酸的非编码小RNA，通过与靶mRNA的互补配对而在转录后水平上对基因的表达进行负调控，导致mRNA的降解或翻译抑制。到目前为止，已报道有几千种miRNA存在于动物、植物、真菌等多细胞真核生物中，进化上高度保守。
这一小分子近期发展迅猛，在药物筛选方面提供了一种飞跃性的前沿遗传工具，许多临床实验都在癌症治疗，病毒感染和退行性疾病的治疗上利用了RNAi基因沉默方法，同时由于这一领域的异常活跃，相关的能提供试剂和签约服务的公司也发展迅速，形成了一个网络。就这些方面，近期《Nature》杂志以“Small RNAs: Delivering the future ”为题，作为“Technology Features”进行了报道。
从癌症治疗到AIDS防治，也许未来的药物可以依赖于一种小RNA分子，但是科学家们现在的首要工作是如何去分析出这些成分。
英文原文：
Nature 450, 1117-1120 (13 December 2007) | doi:10.1038/4501117a; Published online 12 December 2007
Small RNAs: Delivering the future
Nathan Blow1
Abstract
Drugs to treat diseases from cancer to AIDS could soon rely on short strands of RNA for their effects. But scientists must first work out how to navigate these fragments around the body. Nathan Blow reports.
The remarkable ability of short sequences of synthetic RNA to interfere with messenger RNA and thereby silence the activity of specific genes has proved incredibly helpful to geneticists wrestling with genetic function. And the push to harness this RNA interference (RNAi) for therapeutic use is now beginning to make headway. In the six years since the first paper reporting RNAi gene silencing in mammals was published1, at least six therapeutic programmes based on the concept have moved into clinical trials.
"Progress in the field of RNAi therapeutics has occurred remarkably fast," says John Maraganore, president and chief executive of Alnylam Pharmaceuticals in Cambridge, Massachusetts. But delivering the sequences remains a problem. Initial clinical trials relied on 'local delivery', directly introducing short interfering RNAs (siRNAs) into the specific tissue they were to treat. But for true therapeutic value, the siRNAs need to be introduced systemically.
"Systemic delivery is the major issue right now," says Alan Sachs, vice-president for RNA therapeutics based at Sirna Therapeutics, a wholly owned subsidiary of Merck in San Francisco.
Getting a small RNA to interfere with the right messenger RNA in the correct tissue and cell type at a safe, therapeutic level by systemic administration requires an exquisite degree of control — creating the need for different delivery vehicles and potentially even specialized targeting strategies. Animal studies2 have shown that it is possible for siRNAs delivered systemically to silence target genes. "What we have learned over the past couple of years is that systemic delivery of RNAi can be achieved, and there are a variety of methods that can be used to achieve it," says Maraganore. But he is also quick to note that there is no simple solution.
"If you inject naked siRNA into the blood, under normal pressure, it doesn't work," says Daniel Anderson of the Center for Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge. Yet naked siRNA delivered directly into the lungs to treat respiratory syncytial virus (RSV) can profoundly reduce viral replication. This contrast highlights the chasm between local and systemic delivery of synthetic siRNAs.
Local delivery
Alnylam focused on local delivery when it began to develop RNA-based therapeutics. Its treatment for RSV in the lungs uses an inhaled synthetic RNA that triggers the destruction of a protein essential for the virus's replication. Inhalation allows high local concentrations of the RNA to be achieved, says Maraganore, while also taking advantage of naturally occurring mechanisms, such as pinocytosis, for uptake into the target cells.
ENCAPSULA NANOSCIENCES
Liposomes offer one way of achieving systemic delivery of siRNAs.
Work by researchers at the company has also helped shed light on systemic delivery. In a 2004 study2, they affirmed for the first time the potential 'drug-like' properties of siRNAs when delivered systemically. The team used a synthetic RNA conjugated to cholesterol and stabilized with a partial phosphorothioate backbone and 2'-O-methyl sugar modifications on both the sense and antisense strands of the RNA.
Since this study, both lipid- and polymer-based vehicles for systemic delivery of siRNAs have been developed and tested. At Polyplus-transfection in Illkirch, France, researchers have taken advantage of the difference between cationic polymers and cationic lipids for systemic delivery to different organs. "We are interested in delivery to the lung and have used systemic administration of the cationic polymer polyethylenimine for delivery," says Patrick Erbacher, the company's chief scientific officer. "But for tumour injections, we use either a cationic polymer or a cationic lipid formulation."
With siRNAs conjugated to lipids or encapsulated in liposomes or lipid nanoparticles, several companies have achieved stable and efficient systemic delivery to organs including the liver, pancreas, kidneys and even to some types of tumour. And polymers that can complex with siRNA can deliver the short sequences to organs such as the lungs, spleen and kidneys.
全文链接：
http://www.nature.com/nature/journal/v450/n7172/full/4501117a.html
