Pharmacological Chaperone Therapy for the Treatment of Lysosomal Storage Disorders

We have explored the feasibility of therapeutic approaches for lysosomal storage disorders (LSDs), using small molecule drugs, specifically pharmacological chaperones. Pharmacological chaperone therapy (PCT) is based on using ligands to prevent misfolding and degradation of mutated proteins. We have provided data supporting the use of PCT in Pompe disease (PD), a rare metabolic myopathy, and in Fabry disease (FD), an X-linked inherited disease associated with progressive, life-threatening manifestations (renal failure, cardiomyopathy, premature myocardial infarctions, stroke). Our studies have shown that chaperones rescue mutated GAA in patients that express responsive forms of GAA, and thus may be an alternative treatment to ERT. We have also provided evidence that chaperones are also useful in enhancing the efficacy of rhGAA preparations used for ERT with a synergistic effect. Our pre-clinical studies on the synergy between ERT and PCT have been translated into a clinical trial. This is the first trial based on combining ERT with a chaperone. We evaluated the effects of the chaperone N-butyldeoxynojirimycin on blood GAA activity in 13 PD patients. The treatment combination resulted in significantly increased GAA activity in patients’ blood, suggesting that the chaperone enhanced the stability of the recombinant enzyme. We also aim to identify novel allosteric pharmacological chaperones.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.