title: A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy.
abstract: Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.
authors: 1] Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy [2] Telethon Institute of Genetics and Medicine, Napoli, Italy.
authors: Giancarlo
authors: G
authors: Parenti
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Simona
authors: S
authors: Fecarotta
authors: Dipartimento NeuroFarba Universita' degli Studi di Firenze, Firenze, Italy.
authors: Giancarlo
authors: G
authors: la Marca
authors: Telethon Institute of Genetics and Medicine, Napoli, Italy.
authors: Barbara
authors: B
authors: Rossi
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Serena
authors: S
authors: Ascione
authors: UO Malattie Metaboliche e Muscolari Ereditarie, Ospedale Pediatrico Meyer, Firenze, Italy.
authors: Maria Alice
authors: MA
authors: Donati
authors: UO Patologia Muscolare e Neuro-immunologia, Fondazione IRCCS, Istituto Neurologico Besta, Milano, Italy.
authors: Lucia Ovidia
authors: LO
authors: Morandi
authors: Fondazione IRCCS Istituto Neurologico Mondino, Pavia, Italy.
authors: Sabrina
authors: S
authors: Ravaglia
authors: Fondazione IRCCS Istituto Neurologico Mondino, Pavia, Italy.
authors: Anna
authors: A
authors: Pichiecchio
authors: Dipartimento NeuroFarba Universita' degli Studi di Firenze, Firenze, Italy.
authors: Daniela
authors: D
authors: Ombrone
authors: UO Malattie Metaboliche e Muscolari Ereditarie, Ospedale Pediatrico Meyer, Firenze, Italy.
authors: Michele
authors: M
authors: Sacchini
authors: UO Patologia Muscolare e Neuro-immunologia, Fondazione IRCCS, Istituto Neurologico Besta, Milano, Italy.
authors: Maria Barbara
authors: MB
authors: Pasanisi
authors: Dipartimento di Medicina Molecolare, Università di Pavia, Pavia, Italy.
authors: Paola
authors: P
authors: De Filippi
authors: Dipartimento di Medicina Molecolare, Università di Pavia, Pavia, Italy.
authors: Cesare
authors: C
authors: Danesino
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Roberto
authors: R
authors: Della Casa
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Alfonso
authors: A
authors: Romano
authors: Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors: Carmine
authors: C
authors: Mollica
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Margherita
authors: M
authors: Rosa
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Teresa
authors: T
authors: Agovino
authors: Telethon Institute of Genetics and Medicine, Napoli, Italy.
authors: Edoardo
authors: E
authors: Nusco
authors: 1] Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy [2] Telethon Institute of Genetics and Medicine, Napoli, Italy.
authors: Caterina
authors: C
authors: Porto
authors: Dipartimento di Scienze Mediche Traslazionali, Sezione di Pediatria, Università "Federico II", Napoli, Italy.
authors: Generoso
authors: G
authors: Andria
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D059788:Dried Blood Spot Testing; D004357:Drug Synergism; D056947:Enzyme Replacement Therapy / Q000379:methods; D004795:Enzyme Stability; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000097:blood* / Q000188:drug therapy*; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D055815:Young Adult; D000520:alpha-Glucosidases / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; C509951:GAA protein, human; D000520:alpha-Glucosidases