Multiplexed in vivo optimisation of non-toxic gene transfer agents.

将物质放入细胞是非常具有挑战性的，因为细胞具有天然屏障，可以阻止大多数外来物质的进入。然而，能够将特定的遗传物质（DNA）放入人体细胞将具有巨大的医学应用。例如，这种遗传物质可以用来纠正有缺陷的基因（如囊性纤维化），对抗病毒感染或防止癌症的生长。该项目旨在开发工具，使快速发现能够有效地将DNA传递到细胞中的传递设备成为可能。其中一种工具是所谓的多路分析，我们将准备100种不同的DNA和载体材料组合，然后以一种同时评估100种不同化合物的方式分析这些组合。胜利者将是进入细胞效率最高的化合物。多路复用当然是一个众所周知的术语，涉及到有多个屏幕的电影院。这里的类比是，我们有100部正在播放的电影（类比是，这些是我们正在研究的100个公式），我们承认10000人（这些类比是细胞），并分析人（细胞）的分布，即最喜欢的电影是什么。该项目的第二个要素是开发无毒和自然降解的输送装置。将我们的电影类比进一步延伸，我们寻找的是能给观众留下积极持久印象的电影（当然不一定是拥有最多观众的电影！）囊性纤维化（CF）是一种影响英国7000多人的遗传性疾病。患者经常遭受细菌感染，导致越来越多的肺损伤。虽然CF治疗已经有了很大的进步，但肺部疾病会导致早期死亡，出生时的预期寿命约为30岁。基因治疗，包括用工作拷贝替换有缺陷的CF基因，有可能极大地改善CF患者的健康状况。基因治疗提供了改善病人的可能性？这将大大减少美国的前景，并减少疾病的经济影响。这个项目的重点是为治疗囊性纤维化生产更好的基因治疗配方。然而，间接地，新的基因转移试剂的配方和表征将进入一般的基因治疗领域，这些试剂可能会在其他遗传疾病的治疗中得到应用。

Putting material into cells is very challenging as cells have natural barriers that prevent the entry of most foreign materials. However being able to put specific genetic material (DNA) into human cells would have immense medical applications. For example the genetic material could be used to correct a defective gene (such as in cystic fibrosis), fight viral infection or prevent the growth of cancers.This project aims to develop tools that allow the rapid discovery of delivery devices that enable the efficient delivery of DNA into cells. One such tool is so-called multiplexed analysis where we will prepare 100 different combinations of DNA and carrier materials and then analyze these in such a way in which a hundred different compounds will be evaluated at one time. The winner will be compound that enters the cell most efficiently. Multiplexing is of course a well known term in relations to movie theatres with multiple screens. The analogy here is that we have 100 movies running (the analogy is that these are the 100 formulations we are examining), we admit 10,000 people (these by analogy are the cells) and analyze the distribution of people (cells) i.e. what was the most favourite film. A second element of this project is the development of delivery devices that are non-toxic and degrade naturally. Extending our movie analogy further we are looking for the one that will leave a positive lasting impression on the viewer (which may not of course be the movie that had the greatest audience!). Cystic fibrosis (CF) is a genetic disease affecting over 7000 individuals in the UK. Patients suffer frequent bacterial infections which lead to more and more lung damage. While there have been great improvements in CF treatment, lung disease leads to early death with a life expectancy at birth of about 30 years. Gene therapy, involving replacement of the defective CF gene with a working copy, has the potential to greatly improve the health of CF patients. Gene therapy offers the possibility of improving the patient?s prospects dramatically as well as reducing the disease s economic impact. This project is focused on producing better gene therapy formulations for the treatment of cystic fibrosis. However, indirectly, the formulation and characterization of novel gene transfer reagents would feed into the gene therapy field in general, and such reagents may find application in the treatment of other genetic disorders.