Leader: Antonio Pisani; Other collaborator: Daniela Sorriento
Fabry disease is a rare multisystemic lysosomal storage disorder characterized by a wide spectrum of clinical manifestations, including cardiovascular, renal, and neurological involvement, as well as chronic pain and reduced quality of life. In addition to supportive therapies aimed at managing symptoms resulting from organ damage, approved treatments for Fabry patients primarily focus on restoring enzymatic activity, which is the main, but not the only, pathogenic mechanism of the disease.
Within the framework of WP3 of Spoke 4, which focuses on the integration of digital technologies in the life-course approach for active and healthy aging, it is essential to explore the issue of frailty in Fabry disease patients. This population represents a new frontier for aging and multidimensional health management studies, especially in light of increased life expectancy due to novel therapies. The assessment of frailty in these patients allows for:
This new task aligns with WP3 activities related to identifying multidimensional approaches for maintaining health in frail patients, exploring the underlying molecular mechanisms, and creating digital tools for integrated risk profiling, with related monitoring and personalized interventions. This task will commence in January 2025, supported by the involvement of new professionals joining as Age-It fellows.
Brief description of the activities and of the intermediate results
In a murine model of Fabry disease (FD), we are investigating the impact of exercise on maladaptive metabolic remodeling, physical performance, and organ damage. The model used is a humanized FD mouse (hR301Q α-Gal A Tg/KO), which exhibits Gb3 accumulation, impaired exercise tolerance, skeletal muscle alterations, and systemic metabolic changes.
From 2 months of age, both FD and WT mice undergo a treadmill-based exercise training protocol, three times per week. After 3 months, assessments are carried out comparing trained FD mice with naïve and ERT-treated FD groups. Physical performance is measured by total treadmill distance and voluntary wheel-running activity.
Skeletal muscle samples are used for metabolomic profiling, focusing on Krebs cycle intermediates. Mitochondrial function is evaluated via oxygen consumption (Seahorse) and expression of ETC components and mitochondrial biogenesis regulators (PGC1α) by western blot. Organ damage is assessed through histological analysis of kidneys, lungs, and heart, alongside plasma creatinine and LysoGb3 levels. The study also aims to identify novel metabolic targets for FD treatment.
Main policy, industrial and scientific implications
This study may provide insights into the potential of non-pharmacological interventions, such as exercise, in modulating disease progression in Fabry disease. Comparing exercise and ERT may inform integrated therapeutic approaches. Results could support the development of complementary strategies targeting mitochondrial dysfunction and systemic metabolism, with implications for clinical management and future research into FD and other lysosomal storage disorders.
Brief description of the activities and of the intermediate results
The protocol has been approved by the local ethical committee. Over the past months we started to collect data from our murine model of Fabry disease (FD) to investigate the mechanisms underlying metabolic and mitochondrial dysfunction. Mouse embryonic fibroblasts isolated from FD mice exhibited impaired mitophagy, reduced mitochondrial respiration, and increased production of reactive oxygen species (ROS). In addition, PGC1α levels and mitochondrial DNA copy numbers were downregulated, indicating compromised mitochondrial biogenesis. A significant reduction in electron transport chain complexes, particularly complexes III and IV, was observed in FD cells, together with decreased cellular ATP content. These alterations in mitochondrial homeostasis and cellular energetics were associated with increased fatigability in FD mice and the systemic release of markers of metabolic stress, including lactate and mitochondria-related miRNAs.
Main policy, industrial and scientific implications
This study may provide insights into new disease relative mechanisms. Results could support the development of complementary strategies targeting mitochondrial dysfunction and systemic metabolism, with implications for clinical management and future research into FD and other lysosomal storage disorders.
Brief description of the activities and of the intermediate results
To evaluate the impact of exercise on maladaptive metabolic remodeling, physical performance, and organ damage in Fabry disease (FD), we initiated a treadmill-based exercise training protocol in FD mice, performed three times per week for two months. At the end of the training period, physical performance was assessed by measuring total treadmill distance, voluntary wheel-running activity, and weight-lifting capacity. Data will be collected and analyzed in the next trimester.
On the other side, we started enrolling patients with Fabry disease in a adaptive physical activity program. Over the past months, we enrolled the first patients who were evaluated by means of different tests to assess lower and upper limbs strength, flexibility, equilibrium, exercise capacity.
Main policy, industrial and scientific implications
This study may provide insights into the potential of non-pharmacological interventions, such as exercise, in modulating disease progression in Fabry disease. Comparing exercise and ERT may inform integrated therapeutic approaches. Results could support the development of complementary strategies targeting mitochondrial dysfunction and systemic metabolism, with implications for clinical management and future research into FD and other lysosomal storage disorders.
Brief description of the activities and of the intermediate results
Analysis of the first set of collected samples has been complete. Trained FD mice exhibited a significant improvement in aerobic exercise tolerance, whereas muscle strength (weight-lifting capacity) did not change. Echocardiographic assessment of cardiac morphology and function revealed no major exercise-induced modifications in FD mice. In skeletal muscle from FD mice, exercise training significantly increased the expression of key regulators of mitochondrial biogenesis, including PGC1α and NRF1, as well as components of the electron transport chain (ETC) and HIF-1. Organ damage was evaluated by histological analysis of the kidneys, lungs, and heart, together with measurements of plasma creatinine and LysoGb3 levels.
On the clinical standpoint, we proceeded with patients’ enrollment for the adaptive physical activity program and started to analyze data, to get the first preliminary results.
Main policy, industrial and scientific implications
This study may provide insights into the potential of non-pharmacological interventions, such as exercise, in modulating disease progression in Fabry disease. Comparing exercise and ERT may inform integrated therapeutic approaches. Results could support the development of complementary strategies targeting mitochondrial dysfunction and systemic metabolism, with implications for clinical management and future research into FD and other lysosomal storage disorders.
EXPECTED OUTPUTS
Multidimensional Model for Frailty Assessment in Fabry Patients:
Pilot Study Focused on Integrating Digital Technologies into Healthcare Services for Fabry Patients:
Scientific and Dissemination Outputs: