Dr. Andrea Armani, University of Zürich

Abstract

Pompe disease (PD) is a rare genetic disorder stemming from inactivating mutations in the GAA gene; as a consequence, reduced or null acid maltase activity leads to pathological glycogen accumulation in lysosomes of several tissues. Due to the impairment of lysosomal function, PD has been described as the first lysosomal storage disease (LSD), affecting 1 in 40,000 live births. In the infantile form, lysosomal glycogen accumulation causes a severe cardiomyopathy that can be successfully reverted by enzyme replacing therapy (ERT); however, both in infantile and late onset forms (LPOD), a severe, ERT-resistant and progressive skeletal muscle degeneration and weakness is forcing patients to wheelchairs and mechanical ventilation. Unfortunately, to date, respiratory failure is still the main cause of death in LOPD patients, even if pharmacologically treated.

Studies clarifying the pathogenic cascade guided the optimization of available therapies and the development of next-generation ERT; however, no advancements in the systematic assessment of lysosomal signaling alterations during PD progression has been made due to major technical challenges in the isolation of functional organelles. Thus, it is imperative to characterize alterations in lysosomal composition, interactome and function to deeper clarify PD pathogenesis. To achieve this, I will implement 3 specific aims within this project:

1. Optimization of LysoIP method to characterize lysosomal signals from pathological heart, diaphragm and skeletal muscles of GAA null LysoIP mice;
2. Determination of precocious lysosomal signaling abnormalities contributing to PD pathogenesis, through proteomic and metabolomic profiling of purified lysosomes. Indeed, the main hypothesis is that glycogen accumulation alone is not sufficient to explain the complexity of the disease;
3. Identification of ERT resistant signals as new targets for pharmacological intervention. Indeed, ERT resistant aspects are the real challenge for PD treatment, especially in relation to skeletal muscle.

Summarizing, this ambitious project aims to fill fundamental gaps in the comprehension of the hidden signaling events at the onset of GAA deficiency pathogenesis, with the final goal to serve as a platform for new therapies development.