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

标题：开发一种针对哮喘基因ADAM33的新药作为一种新的疾病修饰哮喘疗法需要：英国有540万哮喘患者，它是儿童最常见的呼吸道疾病。尽管通常被认为是可控的，但在英国，平均每天仍有3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。建议的解决方案：ADAM33是一种哮喘易感基因，与呼吸道的“抽动”(高反应性)密切相关，表明在呼吸道结构或功能的变化中发挥了作用。我们和其他小组已经证明，哮喘患者肺中ADAM33的含量增加，并且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证明，ADAM33在小鼠模型哮喘样疾病的发展过程中起着重要作用，在这种模型中，缺乏ADAM33的小鼠可以免受疾病的关键方面的影响，包括导致人类哮喘症状的呼吸道“抽搐”和过敏性炎症。我们的数据表明，ADAM33是未来新型哮喘疗法的有效靶点，可以真正改变疾病的严重程度。开发计划：我们现在已经开发出一种新的哮喘药物，抗ADAM33寡核苷酸(A33-Olios)，专门针对哮喘患者的ADAM33。在我们的小鼠模型中试验这些新疗法的早期研究表明，它们可以作为吸入性药物给予，在一次吸入后四周内非常有效，并且在减少肺部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了这种A33-寡核苷酸，可以抑制与完全缺乏ADAM33的小鼠的结果类似的呼吸道的“抽动”。我们现在的目标是在人源化的ADAM33哮喘小鼠模型中进一步开发这种针对人类ADAM33的新药。在我们确认A33-寡核苷酸疗法在治疗哮喘方面有效之后，特别是在大多数更严重的哮喘病例的标志--呼吸道“抽动”--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，我们将申请首次在人体试验中使用A33-寡核苷酸。我们相信，ADAM33特异的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的特征。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无效的患者。

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.