TY - JOUR
T1 - A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy
AU - Parenti, Giancarlo
AU - Fecarotta, Simona
AU - la Marca, Giancarlo
AU - Rossi, Barbara
AU - Ascione, Serena
AU - Donati, Maria A lice
AU - Morandi, Lucia O vidia
AU - Ravaglia, Sabrina
AU - Pichiecchio, Anna
AU - Ombrone, Daniela
AU - Sacchini, Michele
AU - Pasanisi, Maria B arbara
AU - De Filippi, Paola
AU - Danesino, Cesare
AU - Della Casa, Roberto
AU - Romano, Alfonso
AU - Mollica, Carmine
AU - Rosa, Margherita
AU - Agovino, Teresa
AU - Nusco, Edoardo
AU - Porto, Caterina
AU - Andria, Generoso
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
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U2 - 10.1038/mt.2014.138
DO - 10.1038/mt.2014.138
M3 - Article
C2 - 25052852
AN - SCOPUS:84964314262
VL - 22
SP - 2004
EP - 2012
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 11
ER -