Estimulação de MSCs para o tratamento da Doença de Parkinson – novas abordagens terapêuticas e biomarcadores de resposta terapêutica

Parkinson’s Disease stands as the second most prevalent neurodegenerative disorder and the foremost movement disorder. Despite decades of studies, it still lacks molecular biomarkers crucial for diagnosis support, prognostic identification during the prodromal phase (prior to symptom onset – Figure 5), and monitoring biomarkers to address the efficacy of therapeutic approaches on the neurodegenerative process versus symptomatic relief. This project undertakes an integrated approach to address these critical gaps by pursuing the following objectives: #1 – Validate previous plasma biomarkers across diverse animal models during the prodromal phase and symptomatic onset (Tasks 2, 3, 4 and 5) The ability to predict disease development, such as the newborn screening or pre-diabetic detection, enhances therapeutic efficacy significantly compared to addressing established diseases with profound tissue alterations and pronounced symptoms. The principle has to become available for neurodegenerative disorders, as PD. Therefore, this objective encompasses both prognostic and diagnostic biomarker lines utilizing cellular secretome, plasma samples from various PD animal models, and subsequent correlation to our panel of human biomarkers (6, 9) to unveil potential cross-species PD biomarkers. #2 – Employ differently primed MSCs to mitigate the neurodegenerative process (Tasks 2, 3, 4 and 5) Numerous prior studies, including those from our team and others, have explored the use of MSCs and/or their secretome, even under hypoxia priming, to decelerate PD progression. What sets this project apart lies in the consolidation of different approaches applied to MSCs (priming), their method of administration, monitoring their homing in diverse PD animal models, and the correlation of an extensive dataset. This project marks the first instance where comprehensive information on MSCs in PD models will combine multiple tissue proteomics (brain and plasma), local inflammatory biomarkers (glial reactivity), electrophysiology, and animal behavior data in a holistic approach. #3 – Monitor local and peripheral fluid rescue biomarkers (Tasks 3, 4 and 5) It is imperative to monitor the therapeutic potential of cell-based products to dispel speculation and misconceptions within the scientific, clinical, and social communities. This task aims to generate factual evidence by monitoring brain tissue and plasma (with multiple time points) to trace the biochemical profile correlating with neuroprotection mechanisms. Molecular signatures from brain and plasma (proteomics and metabolomics) will be acquired, and a biomarker data analysis approach will be employed to determine sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Proteins/metabolites demonstrating at least 80% sensitivity and specificity will be deemed useful for classifying animals with PD. In conclusion, this project aims to validate plasma biomarkers across diverse animal models, investigate the efficacy of differently primed MSCs in attenuating the neurodegenerative process, and assess local and peripheral fluid rescue capacities to enhance our ability to diagnose and treat Parkinson's Disease. These aspects, currently absent in clinical practice, hold the potential to revolutionize the paradigm for PD patients’ treatment.