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

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.

Acrodysostosis type 2 (ACRDYS 2) is a rare developmental skeletal dysplasia disorder characterised by distinct symptoms such as a small gestational size, short stature in adulthood, obesity, brachydactyly, facial dysostosis, advanced bone age, progressive parathyroid hormone resistance, thyroid hormone resistance and neurocognitive impairment. ACRDYS 2 is an autosomal dominant condition caused by single nucleotide polymorphism (SNP) missense mutations in the phosphodiesterase-4 subtype D (PDE4D) gene that enhance enzyme activity. Whilst the genetics behind ACRDYS 2 are well established, it is not clear how the mutations contribute molecularly and phenotypically to the range of symptoms observed in patients. Furthermore, there are several pharmacological PDE4D inhibitors that could be evaluated for their therapeutic potential in ACRDYS 2. Unfortunately, there were no animal models of the disease to allow the undertaking of these fundamental and translational investigations. We have recently generated a novel mouse model for ACRDYS 2 with a SNP reflecting the human PDE4D S190A mutation (S185A in mice) that displays phenotypes reflecting the human condition such as reduced size and weight as well as aberrant cognitive function. These mice will be fully characterised for canonical ACRDYS 2 pathological hallmarks. The therapeutic potential of existing PDE4D and novel mutant-selective PDE4D (proteolysis targeting chimera (PROTACs)) inhibitors will also be evaluated. Finally, we will perform RNA-sequencing on pathologically affected tissues to identify shared and tissue-specific dysregulated genes and pathways as well as determine the extent of their restoration following treatment with PDE4D inhibitors. This mouse model will be an invaluable tool for researchers, clinicians and patients to help better understand the pathophysiology of ACRDYS 2 as well as identify treatment strategies for ACRDYS 2 and other conditions characterised by aberrant PDE4D activity.