Long-lasting correction of the basic defect in cystic fibrosis

由遗传性疾病囊性纤维化（CF）引起的气道疾病尚无法预防。目前的治疗方法只能限制逐渐增加的肺部疾病，而且费用昂贵。我们的新基因治疗技术将一种校正基因引入到受影响的气道细胞中，并已在CF小鼠的第一次试验中发挥了作用。小鼠气道用于测试效果是否可靠、有效、持续时间是否足够长。这种基因是通过特殊的病毒递送颗粒引入气道的，经过气道调节使其能够接受这些颗粒。该方法适用于正常小鼠和CF小鼠；单次注射就能实现持久的基因转移，似乎能影响所有气道细胞类型。基因转移也可能发生在气道干细胞中，即生长气道表面所有细胞的母细胞。到目前为止，还没有人能够以这种方式产生长时间的基因转移，也没有人能够将基因转移到活气道中的干细胞中。在我们在大型动物身上进行安全性和有效性试验之前，或者考虑进行人体临床试验之前，我们必须调查很多事情。我们需要确切地了解条件调节因子是如何起作用的，它是否安全；测量一下基因校正在动物身上能持续多久；决定我们是否可以在不因可能发生的炎症或免疫反应而失去效力的情况下（如果需要）重新给动物注射；并决定气道干细胞在基因转移过程中的重要性。由于很难测量CF气道中的基因校正，我们还将测试我们开发的新方法，以测量CF气道中基因校正的效果。这个项目的发现将使我们能够发展我们的方法，我们可以在更大的动物身上进行测试，提供一个强大的、持久的基因校正，这将是安全的，可以在人体临床试验中进行测试。

The airway disease caused by the genetic disease cystic fibrosis (CF) is not yet preventable. Current treatments can only limit the gradually-increasing lung disease and is costly. Our new gene therapy technique introduces a correcting gene into affected airway cells, and it has already worked in the first tests in mice bred with CF. Airways in mice are used to test whether the effect is reliable, effective, and lasts long enough to be useful. The gene is introduced into the airway using special virus delivery-particles, after conditioning the airway to make it receptive to the particles. The method works in normal mice and in CF mice; it gives long lasting gene transfer from a single dose and seems to affect all airway cell types. The gene transfer may also be occurring in airway stem cells, i.e. the mother cells from which grow all the cells of the airway surface. Until now, no-one else has been able to produce prolonged gene transfer in this way, nor arrange gene transfer into stem cells in live airways. There are now a number of things that we must investigate before we could conduct safety and effectiveness trials in larger animals, or consider moving into clinical trials in humans. We need to understand exactly how our conditioning agent works and is it safe; measure how long the gene correction can last actually in our animals; decide if we can we re-dose animals (if needed) without losing effectiveness because of inflammation or immune responses that might occur; and decide how important the airway stem cells are in producing the length of the gene transfer. Because it has been difficult to measure gene correction in CF airways, we will also test new ways we have developed to measure how well the gene correction works in CF airways. The findings of this project will allow us to develop our method to where we can test it in larger animals, to provide a strong, long-lasting gene correction that will be safe for testing in human clinical trials.