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个纠正基因引入受影响的气道细胞，它已经在用CF繁殖的小鼠的第一次测试中起作用。小鼠的气道被用来测试效果是否可靠，有效，并持续足够长的时间来使用。在调节气道使其接受颗粒后，使用特殊的病毒递送颗粒将基因引入气道。该方法在正常小鼠和CF小鼠中起作用;它从单次剂量提供持久的基因转移，似乎影响所有气道细胞类型。基因转移也可以发生在气道干细胞中，即从其生长气道表面的所有细胞的母细胞。到目前为止，还没有人能够以这种方式产生长期的基因转移，也没有人能够将基因转移到活气道中的干细胞中。在我们能够在较大的动物身上进行安全性和有效性试验之前，或者考虑进入人体临床试验之前，我们必须调查一些事情。我们需要确切地了解我们的调节剂是如何工作的，它是否安全;测量基因校正在我们的动物中实际上可以持续多久;决定我们是否可以重新给动物注射（如果需要的话），而不会因为可能发生的炎症或免疫反应而失去效果;并决定气道干细胞在产生基因转移的长度方面有多重要。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来测量CF气道中基因校正的效果。该项目的发现将使我们能够开发我们的方法，以便我们可以在较大的动物中进行测试，以提供一种强大，持久的基因校正，这对于人类临床试验的测试是安全的。

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.