Preclinical efficacy and safety studies of ADAM33 oligonucleotides as new disease-modifying asthma therapy

题目：开发一种针对哮喘基因ADAM33的新型药物，作为一种新的疾病改善哮喘疗法。需求：在英国有540万哮喘患者，这是儿童中最常见的呼吸系统疾病。尽管哮喘通常被认为是可控的，但在英国平均每天仍有三人死于哮喘发作，目前的哮喘治疗方法都无法预防或治愈这种疾病；因此，开发新的治疗方法仍然是当务之急。提出的解决方案是：ADAM33是一种哮喘易感基因，与气道的“抽搐”（超反应性）密切相关，这表明它在气道结构或功能的改变中起作用。我们和其他研究小组已经证明，哮喘患者的肺部ADAM33增加，并且发现ADAM33的数量与患者的疾病严重程度和肺功能异常有关。我们的研究小组进一步表明，ADAM33在小鼠模型中哮喘样疾病的发展中很重要，缺乏ADAM33的小鼠免受疾病的关键方面的影响，包括气道“抽搐”和气道过敏性炎症，这两种疾病都会导致人类的哮喘症状。我们的数据表明，ADAM33是未来新型哮喘治疗的有效靶点，可以真正改变疾病的严重程度。开发计划：我们目前已经开发了一类新的哮喘药物，抗ADAM33寡核苷酸（A33-oligos），专门针对哮喘中的ADAM33。在我们的小鼠模型中试验这些新疗法的早期研究表明，它们可以作为一种吸入药物，在单次吸入后的四周内都非常有效，而且它在减少肺部ADAM33的数量方面非常有效。在最初的初步实验中，我们在哮喘小鼠模型中使用这种A33-oligo，可以抑制气道的“抽搐”，与完全缺乏ADAM33的小鼠的结果相似。我们现在的目标是在人源化ADAM33哮喘小鼠模型中进一步开发这种针对人类ADAM33的新型药物。在我们确认A33-oligo疗法对治疗哮喘，特别是大多数严重哮喘病例的气道“抽搐”是有效的之后，我们将在更大的动物身上进行安全性研究。如果这种新的哮喘药物在这些动物身上是安全的，我们将首先申请在人体试验中使用A33-oligos。我们相信，ADAM33特异性寡核苷酸将使我们能够针对目前哮喘药物无法治疗的疾病特征。因此，我们的最终目标是开发一种新的哮喘疗法，帮助那些对现有药物没有反应的哮喘患者。

Title: Development of a new class of drug targeting the asthma gene ADAM33 as a new disease-modifying asthma therapyThe need: There are 5.4 million people with asthma in the UK and it is the most common respiratory disease in children. Although often considered controllable, on average three people still die from an asthma attack in the UK every day, and none of the current asthma treatments are able to prevent or cure the disease; therefore, the development of new treatments remains a priority.The proposed solution: ADAM33 is an asthma susceptibility gene that is strongly associated with "twitchiness" (hyper-responsiveness) of the airways suggesting a role in the change of the structure or function of the airways. We and other groups have shown that ADAM33 is increased in the lungs of asthmatic patients and that the amount of ADAM33 found correlates with patient's disease severity and abnormal lung function. Our research group has further shown that ADAM33 is important in the development of asthma-like disease in mouse models, where mice lacking ADAM33 are protected from key aspects of the disease, including the airway "twitchiness" and allergic inflammation in the airway both of which contribute to asthma symptoms in people. Our data suggest that ADAM33 is a valid target for future, novel asthma therapies that can make a real difference in the severity of the disease. Development plan: We have now developed a new class of asthma drug, anti-ADAM33 oligonucleotides (A33-oligos), to specifically target ADAM33 in asthma. Early investigations trialling these new therapies in our mouse models have shown that they can be given as an inhaled drug, which is highly effective for four weeks after a single inhalation and that it is very potent in reducing the amount of ADAM33 in the lungs. In first preliminary experiments we used this A33-oligo in mouse models of asthma and could suppress the "twitchiness" of the airways similar to the results in the mice that lack ADAM33 completely. Our aim now is to develop this new class of drugs against human ADAM33 further in humanised ADAM33 mouse models of asthma. After we confirm that A33-oligo therapy is effective in treating asthma and in particular the airway "twitchiness" which is a hallmark of most cases of more severe asthma, we will perform safety studies in larger animals. If this new asthma drug is safe in these animals, we will apply for first use of A33-oligos in human trials.We believe that ADAM33 specific oligonucleotides will allow us to target characteristics of the disease which are not treated by current asthma drugs. Thus, our ultimate aim is to develop a new asthma therapy that helps patients whose asthma doesn't respond to currently available medicines.