Estudo integrado para a compreensão de aspetos genéticos e de saúde na doença de Machado-Joseph

1. Develop the STRIDE-X app to capture motor and non-motor symptoms, along with self-assessed disability indicators, in real-life settings. To further support patients, we aim to create and validate a mobile app for real-life disease monitoring, integrating genetic insights and patient-reported outcomes for personalized care. Our app will allow us to identify disease patterns to be useful (i) as endpoints in future clinical trials and (ii) to personalize the type of rehabilitation intervention by the clinicians. STRIDE-X app will include our previously developed digital tests to quantify upper limbs incoordination and three novel digital measures to identify (i) patterns of gait impairment (ii) the risk of pre-falls/falls, and (iii) speech alterations. Furthermore, using their smartphone, patients will be asked to rate items from PROM-ataxia, depression (PHQ-9) and dysphagia (EAT-10). The monitorization of such outcomes, all strongly related to the patient’s quality of life, will allow the signalization of MJD subjects for rehabilitation interventions promoted by physiotherapists, psychologists, speech therapists, and social workers. The STRIDE-X app will also be important to accurately determine the age at which MJD subjects report the first signs/symptoms of the disease. 2. Develop Advanced Tools for determining (CAG)n patterns in genetic testing and research. To advance Machado-Joseph Disease (MJD) research and patient care, we propose a multi-faceted initiative integrating stem cell research and genetic investigation. We will rely on Meka Center facilities and experience to meet this goal. We will establish induced pluripotent stem cell lines (iPSCs) derived from blood samples of Azorean MJD patients, creating a valuable resource for studying disease mechanisms and therapeutic development. Then, profiting from SEEBMO's extensive experience in genetic laboratory testing, we will investigate meiotic and mitotic instability patterns of the CAG repeat in the ATXN3 gene, providing crucial data to improve genetic testing diagnosis, including preimplantation genetic testing. In the Azores, Meka Center can perform all procedures related to reproductive medicine to perform the pre-implantation genetic diagnosis; the genetic test itself, however, needs to be outsourced, a limitation that this project will help overcome. Building on these efforts, we will enhance regional capacity to fully offer ethically valid pre-implantation genetic tests, empowering families with informed reproductive choices. 3. Enhance Patient Engagement and Communication We will collaborate with the Azorean MJD Patient Association (AAADMJ), which will be a member of the project's Advisory Board, to co-design a roadmap for patient engagement activities. This will ensure patient involvement in WP2 and WP2. Our project initiative seeks to create significant scientific and social impacts by effectively balancing the dual priorities of advancing research and addressing critical healthcare needs. On an international scale, we aim to enhance the scientific understanding of Machado-Joseph Disease (MJD) through impactful research outputs, thereby expanding the global knowledge base. Locally, we concentrate on addressing the specific social and healthcare challenges encountered by the Azorean community, utilizing the diverse expertise of our team to deliver targeted and practical solutions.