Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy
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Published:2023-02-25
Issue:5
Volume:24
Page:4548
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Iacobucci Ilaria12ORCID, Hay Mele Bruno3ORCID, Cozzolino Flora12ORCID, Monaco Vittoria12, Cimmaruta Chiara3, Monti Maria12ORCID, Andreotti Giuseppina4ORCID, Monticelli Maria345ORCID
Affiliation:
1. Department of Chemical Sciences, Università degli Studi di Napoli “Federico II”, Complesso Universitario Monte Sant’Angelo, Via Cinthia, 80126 Napoli, Italy 2. CEINGE Biotecnologie Avanzate “Franco Salvatore”, Via G. Salvatore 486, 80131 Napoli, Italy 3. Department of Biology, University of Napoli “Federico II”, Complesso Universitario Monte Sant’Angelo, Via Cinthia, 80126 Napoli, Italy 4. Institute of Biomolecular Chemistry ICB, National Research Council (CNR), Via Campi Flegrei 34, 80078 Pozzuoli, Italy 5. Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania “Luigi Vanvitelli”, Via Vivaldi, 43, 81100 Caserta, Italy
Abstract
Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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