Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy

• Published in: International journal of molecular sciences Vol. 24; no. 5; p. 4548
• Main Authors: Iacobucci, Ilaria, Hay Mele, Bruno, Cozzolino, Flora, Monaco, Vittoria, Cimmaruta, Chiara, Monti, Maria, Andreotti, Giuseppina, Monticelli, Maria
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.02.2023; MDPI
• Subjects: alpha-Galactosidase - metabolism; Analysis; Biopharmaceutics; Brief Report; Disease; Drug approval; Drug development; drug repositioning; Drugs; Enzyme Replacement Therapy - methods; Enzymes; Fabrazyme; Fabry disease; Fabry Disease - metabolism; Fabry's disease; FDA approval; Fibroblasts; Galactose; GLA; Health aspects; Humans; interactome; Isoenzymes - therapeutic use; Medical research; Mutation; Nervous system; Oral administration; Patients; Pharmacology; Recombinant Proteins - therapeutic use; Replagal; Therapeutic applications; Therapeutic targets; Replagal; agalsidase β; Fabry disease; agalsidase α; interactome; drug repositioning; GLA; Fabrazyme
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24054548

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.