Evaluating novel mutant-selective PDE4D PROTACs for the treatment of Acrodysostosis Type 2

肢端骨质疏松症2型(ACRDYS 2)是一种罕见的发育性疾病，患者具有各种症状，如出生体积小、成年后身高矮小、肥胖、面部畸形、骨缺陷、对某些激素的反应减弱和大脑功能受损。基因是我们DNA的一部分，携带着决定一个人特征的信息。当基因出现缺陷时，有时会导致对我们的健康产生负面影响的特征的发展。ACRDYS 2是由一种名为磷酸二酯酶-4亚型D(PDE4D)的基因变化引起的。PDE4D的主要作用是控制体内几个细胞和器官的关键功能的活动。在ACRDYS 2中，PDE4D活性异常升高。虽然ACRDYS 2的原因已被很好地了解，但尚不清楚PDE4D活性增加如何导致患者观察到的一系列症状。此外，有几种药物可以阻断PDE4D活性的增加，这可能会使ACRDYS 2患者受益。不幸的是，直到最近，还没有这种疾病的动物模型来正确和彻底地解决这些研究问题。然而，我们最近为ACRDYS 2创造了一种新的小鼠模型，它具有与人类相似的特征，如体积小、体重减轻和大脑功能异常。我们建议首先进一步描述这种新的小鼠模型，通过观察动物来记录ACRDYS 2患者发生的症状范围。我们还将评估PDE4D阻断药物(现有的和新开发的)对该模型小鼠症状和其他调节分子的影响。这种新颖的小鼠模型将是科学家、医生和患者更好地了解疾病的不同方面的宝贵工具，重要的是，开发可以预防和/或减缓ACRDYS 2和其他PDE4D活性异常增加的症状的新疗法。

Acrodysostosis type 2 (ACRDYS 2) is a rare developmental disease where individuals have a variety of symptoms such as small birth size, short height in adulthood, obesity, facial malformations, bone defects, reduced response to certain hormones and impaired brain functions. Genes are part of our DNA and carry information that determine a person's traits. When genes become defective, this can sometimes lead to the development of traits that have a negative impact on our health. ACRDYS 2 is caused by changes in a gene called phosphodiesterase-4 subtype D (PDE4D). The main role of PDE4D is controlling the activity of key functions across several cells and organs throughout the body. In ACRDYS 2, the activity of PDE4D is abnormally increased. While the cause of ACRDYS 2 is well understood, it is not clear how the increased activity of PDE4D leads to the range of symptoms observed in patients. Furthermore, there are several drugs that block the increased activity of PDE4D that could benefit ACRDYS 2 patients. Unfortunately, until very recently, there were no animal models of the disease to allow these research questions to be correctly and thoroughly addressed. However, we have recently generated a new mouse model for ACRDYS 2 that presents similar features to the human condition such as a small size, reduced weight and abnormal brain function. We propose to firstly further characterise this novel mouse model, whereby the animals will be observed to record the range of symptoms that occur in ACRDYS 2 patients. We will also evaluate the effect of PDE4D blocking drugs (existing and newly developed) on the symptoms and other regulatory molecules in this mouse model. This novel mouse model will be an invaluable tool for scientists, doctors and patients to help better understand the different aspects of the disease and importantly, develop new treatments that can prevent and/or slow down the symptoms in ACRDYS 2 and other conditions where activity of PDE4D is abnormally increased.