Novel therapeutic approaches for the Treatment of Lysosomal Storage Disorders

We have explored the feasibility of therapeutic approaches for lysosomal storage disorders using pharmacological chaperones. Pharmacological chaperone therapy is based on the use of ligands to prevent misfolding and degradation of mutated proteins. We have provided data supporting the use of pharmacological chaperone therapy in Pompe disease, a rare metabolic myopathy, due to acid alpha-glucosidase deficiency, and in Fabry disease, an X-linked inherited disease due to alpha-galactosidase A deficiency that is associated with progressive, life-threatening manifestations. We have also provided evidence that chaperones are able to enhance the efficacy of the recombinant alpha-glucosidase used for enzyme replacement therapy in Pompe disease with a synergistic effect. We translated our pre-clinical studies on this synergy into a clinical trial and are developing this research to provide a new therapy for this disorder. We are also working on the identification of novel allosteric pharmacological chaperones. Allosteric chaperones improve the physical stability of target enzymes without disrupting their catalytic activity. We have demonstrated that N-acetylcysteine is a novel allosteric chaperone for alpha-glucosidase and we are currently studying additional molecules with chaperone properties.

Identification of novel biomarkers for Pompe disease

Identifying biomarkers of patient conditions and response to therapies is a major issue in the management of rare, chronic muscular disorders. Clinical measures currently available for Pompe disease are generally specific for subsets of patients, require specific medical skills and patient collaboration, and can be influenced by inter and intra-investigator variance. We have already identified several micro-RNAs as potential biomarkers for Pompe disease which may be helpful in monitoring disease severity and progression and the effects of treatments. We are now extending the search for additional biomarkers using metabolomic and proteomic approaches.

Other innovative approaches for the treatment of LSDs

Multiple and diverse secondary events are important players in the pathogenetic cascade of lysosomal storage diseases. We are currently focusing our studies on the characterization of these secondary events (with a particular focus on autophagy, and oxidative stress), and on the manipulation of these events as an additional therapeutic strategy.

1. Gene Therapy for Infantile-Onset Pompe's Disease. N Engl J Med, 2025
2. The rapidly evolving view of lysosomal storage diseases. EMBO Molecular Medicine, 2021
3. Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease. EMBO Molecular Medicine, 2021
4. microRNAs as biomarkers in Pompe disease. Genetics in Medicine, 2018
5. Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders. Molecular Therapy, 2015

Complete List of Published Work in MyBibliography