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

ADAM33 寡核苷酸作为新的缓解哮喘疾病疗法的临床前疗效和安全性研究

• 批准号: MR/X013960/1
• 负责人: Hans Haitchi
• 金额: $ 151.65万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX013960%2F1
• 关键词: Preclinical; efficacy; safety; studies; ADAM33

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.

标题：开发一类针对哮喘基因 ADAM33 的新药物，作为一种新的缓解哮喘疾病的疗法 需求：英国有 540 万人患有哮喘，这是儿童中最常见的呼吸道疾病。尽管通常被认为是可控的，但在英国，平均每天仍有三人死于哮喘发作，而且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，与气道的“抽搐”（高反应性）密切相关，表明其在气道结构或功能的变化中发挥作用。我们和其他小组已经表明，ADAM33 在哮喘患者的肺部有所增加，并且 ADAM33 的含量与患者的疾病严重程度和肺功能异常相关。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发挥着重要作用，缺乏 ADAM33 的小鼠可以免受疾病关键方面的影响，包括气道“抽搐”和气道过敏性炎症，这两者都会导致人类哮喘症状。我们的数据表明 ADAM33 是未来新型哮喘疗法的有效靶点，可以真正改善疾病的严重程度。开发计划：我们现已开发出一类新型哮喘药物，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，它们可以作为吸入药物给药，单次吸入后四个星期内非常有效，并且非常有效地减少肺部 ADAM33 的量。在第一个初步实验中，我们在哮喘小鼠模型中使用了这种 A33-oligo，并且可以抑制气道的“抽搐”，类似于完全缺乏 ADAM33 的小鼠的结果。我们现在的目标是在人源化 ADAM33 小鼠哮喘模型中进一步开发针对人 ADAM33 的新型药物。在我们确认 A33-oligo 疗法可有效治疗哮喘，特别是气道“抽搐”（这是大多数更严重哮喘病例的标志）后，我们将在大型动物中进行安全性研究。如果这种新的哮喘药物在这些动物中是安全的，我们将申请在人体试验中首次使用 A33 寡核苷酸。我们相信 ADAM33 特异性寡核苷酸将使我们能够针对当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，帮助哮喘患者对目前可用的药物没有反应。