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Giancarlo Parenti

Associate Investigator, TIGEM

Associate Professor of Pediatrics, Department of Translational Medicine, University of Naples "Federico II", Italy

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, due to acid alpha-glucosidase (GAA) deficiency, characterized by generalized storage of glycogen, and in Fabry disease (FD), an X-linked inherited disease due to alpha-galactosidase (alpha-Gal A) deficiency that is 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. They also improve stability, lysosomal trafficking (FIGURE 1) and maturation of rhGAA.

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.

The search for new chaperones for the treatment of PD.

We also aim to identify novel allosteric pharmacological chaperones. Allosteric chaperones remain bound to enzymes during catalysis without inhibiting target enzymes. We have demonstrated that N-acetylcysteine and related amino acids N-acetylserine and N-acetylglycine are novel allosteric GAA chaperones and interact with a non-catalytic domain of the enzyme (FIGURE 2). These compounds improved physical stability of rhGAA without disrupting its catalytic activity.

Other innovative approaches for the treatment of LSDs.

Our group has also participated in a study on an innovative therapeutic approach for PD, based on the overexpression of TFEB. TFEB overexpression in cultured myoblasts, taken from the mouse model of the disease, induced reduction in size and number of lysosomes, relocation of lysosomes towards the periphery of cells, and reduction of stored glycogen. Increased glycogen clearance, induced by TFEB overexpression, was also shown in vivo. Direct intramuscular injections of an AAV2.1-TFEB vector in gastrocnemius resulted in near-complete clearance of accumulated glycogen. Furthermore, we look for reliable markers (microRNAs) to monitor disease progression and assess clinical efficacy of therapies in LSDs, specifically in PD and FD.


Parenti G, Fecarotta S, la Marca G, Rossi B, Ascione S, Donati MA, Morandi LO, Ravaglia S, Pichiecchio A, Ombrone D, Sacchini M, Pasanisi MB, De Filippi P, Danesino C, Della Casa R, Romano A, Mollica C, Rosa M, Agovino T, Nusco E, Porto C, Andria G (2014). A chaperone enhances blood alpha-gucosidase activity in Pompe disease patients treated with enzyme replacement therapy. Mol Ther. 22(11):2004-12. doi: 10.1038/mt.2014.138.

Parenti G, Moracci M, Fecarotta S, Andria G (2014). Pharmacological chaperone therapy for lysosomal storage diseases. Future Medicinal Chemistry.

Spampanato C, Feeney E, Li L, Cardone M, Lim JA, Annunziata F, Zare H, Polishchuk R, Puertollano R, Parenti G, Ballabio A, Raben N (2013). Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol Med.5(5):691-706. doi:10.4155/fmc.14.40.

Feeney EJ, Spampanato C, Puertollano R, Ballabio A, Parenti G, Raben N. What else is in store for autophagy? Exocytosis of autolysosomes as a mechanism of TFEB-mediated cellular clearance in Pompe disease (2013). Autophagy. 9(7):1117-8. doi: 10.4161/auto.24920. 

Porto C, Ferrara MC, Meli M, Acampora E, Avolio V, Rosa M, Cobucci-Ponzano B, Colombo G, Moracci M, Andria G, Parenti G (2012). Pharmacological Enhancement of alpha-Glucosidase by the Allosteric Chaperone N-acetylcysteine. Mol Ther. 20 (12):2201-2211. doi: 10.1038/mt.2012.152.