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Diaphragm pacing augments ventilatory function in Pompe disease
S86
Abstracts
glycosaminoglycan (GAG) degradation. Enzyme replacement therapies (ERTs) are available for 3 MPS and under development for others. Determination of GAG levels in urine is the most accepted biomarker for MPS, although its usefulness for predicting tissuerelated pathologies is questionable. Recent studies also have monitored serum heparin cofactor II-thrombin complex in MPS patients. Results: We have studied the expression of several inflammation markers in MPS animal models, including TNF-alpha, IL1-beta and others, and found that they are elevated in the serum and synovial fluid from different MPS types and species. We also have found for the first time that the inflammation-related advanced glycan endproducts (AGEs) are elevated in MPS serum, as are several proinflammatory sphingolipids and sphingolipid hydrolases. Importantly, in animals treated by either anti-inflammatory therapy or ERT, a reduction of these biomarkers was found. Conclusions: We propose that inflammation-related molecules are useful biomarkers for MPS and other LSD. Several molecules were identified that are abnormally expressed in the different LSD animal models and were corrected after therapy. doi:10.1016/j.ymgme.2012.11.230
217 Eliminating autophagy by nocturnal enteral feeding reverses muscle dysfunction in late-onset Pompe disease Alfred Slonim, Columbia University Medical Center, New York, NY, USA Pompe disease is the only LSD in which skeletal muscle is the primary target. ERT has produced marked improvement of cardiac function, with much less response in skeletal muscle. Over the last 30 years we have demonstrated that high protein & conditioning exercise therapy (HPET) has been beneficial for stabilizing late-onset patients. Recently it has become apparent that autophagic vacuoles play a critically important role, if not the determinant role, in the pathogenesis of skeletal muscle dysfunction. Suppressing autophagy appeared to be necessary to improve muscle function. A genetically induced skeletal muscle autophagydeficient Pompe disease mouse model was generated, which successfully greatly reduced glycogen accumulation, and eliminated autophagic vacuoles. However, this also resulted in dysfunctional mitochondria, muscle atrophy and early demise of these mice (N. Raben, 2012). In order to decrease starvation induced autophagy, nocturnal enteral feeding (NEF) in addition to HPET during the day, was instituted in two male juvenile-onset patients at 4 years and 1 year of age, with resultant near normal muscle function accompanied by clearance of muscle autophagic vacuoles and glycogen (Muscle & Nerve, 2006). Two further juvenile patients have been similarly treated for the last 2 years, and one adultonset patient treated for the last 8 years, with resultant marked functional improvement. The difference in response of autophagy suppression in the KO mouse model and that of the human studies is probably due to autophagy being genetically completely eliminated in the mouse model, while autophagy was not completely eliminated in the adaptive human model. doi:10.1016/j.ymgme.2012.11.231
218 Diaphragm pacing augments ventilatory function in Pompe disease Barbara Smith, Daniel Martin, David Fuller, Lee Ann Lawson, Lawrence Lottenberg, Saleem Islam, Barry Byrne, University of Florida, Gainesville, FL, USA
Pompe disease is an inherited neuromuscular disorder caused by a deficiency of the enzyme acid alpha glucosidase, which is necessary for the degradation of lysosomal glycogen. The clinical presentation is notable for proximal weakness and ventilatory insufficiency, and respiratory morbidity significantly shortens life-expectancy. Intravenous recombinant enzyme-replacement therapy has been developed to treat the muscle pathology presumed to cause hypoventilation. However, we and others have observed evidence of neuropathology in the phrenic motor system of Pompe patients. Here we report the first known implantation of diaphragm pacemakers into patients with Pompe disease, with a goal of reducing dependency on positivepressure ventilation through augmenting phrenic neural output to achieve effective diaphragm contraction. To date, two subjects (ages 53 and 3 years) with continuous ventilator dependence (4 years and 2 months) underwent implantation of chronic pacing electrodes. Four weeks of pre-operative inspiratory muscle strengthening served as a control period and did not yield measurable improvements in unsupported breathing. After implantation of the pacemaker, patients underwent diaphragm conditioning, which consisted of progressive increases in the stimulation parameters, lengthening of daily pacing, and ventilator weaning. By day 65, pacing could support Patient 1 for 12 h of breathing without mechanical ventilation. Patient 2 reached 18 h of ventilator-free, paced breathing by day 30. Both patients adopted deeper inspiratory volumes (33 and 35% increase) with paced breathing. These initial results indicate that diaphragm pacing may offer an adjunctive treatment to existing pharmacological, exercise, and nutritional therapies to maximize independent breathing. doi:10.1016/j.ymgme.2012.11.232
219 Induction of oral tolerance to N-acetylgalactosamine 6-sulfate sulfatase (GALNS) used for enzyme replacement therapy (ERT) in Morquio syndrome type A Angela Sosa-Molanoa,b, Barbara Kariukic, Alan Knutsenc, Clifford Belloned, Shunji Tomatsue, Luis Barreraf, Adriana Montañoe,g, aSaint Louis University, Saint Louis, MO, United States, bPontificia Universidad Javeriana, Bogota, Colombia, cDepartment of Pediatrics, Divisions of Allergy & Immunology Saint Louis University, St Louis, MO, USA, d Department of Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO, USA, eDepartment of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, MO, USA, fInstituto de Errores Innatos del Metabolismo, Pontificia Universidad Javeriana, Bogotá, Colombia, gDepartment of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, USA Mucopolysaccharidosis type IVA (MPS IVA), or Morquio syndrome type A, is an autosomal recessive disorder caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency that results in the intralysosomal accumulation of keratan sulfate and chondroitin-6sulfate. Like other lysosomal storage disorders (LSD), MPS IVA is a good candidate for enzyme replacement therapy (ERT). The immune response against the infused protein in ERT has been reported as the main limitation in the therapeutic effectiveness. Currently, unspecific immunosuppressive protocols have been evaluated for improving ERT efficacy in which the risk–benefit profile is less clear, due to the associated side effects in the patient. The specific induction of tolerance to proteins used in ERT without associated adverse reactions is crucial for the effectiveness of the treatment. In the present study, the main goal is to induce specific tolerance to GALNS in a mouse model by a natural mechanism before its use in ERT. In a previous report, three GALNS peptides were identified as immunogenic regions within the protein. The peptides induced specific cellular responses to GALNS in
Abstracts
glycosaminoglycan (GAG) degradation. Enzyme replacement therapies (ERTs) are available for 3 MPS and under development for others. Determination of GAG levels in urine is the most accepted biomarker for MPS, although its usefulness for predicting tissuerelated pathologies is questionable. Recent studies also have monitored serum heparin cofactor II-thrombin complex in MPS patients. Results: We have studied the expression of several inflammation markers in MPS animal models, including TNF-alpha, IL1-beta and others, and found that they are elevated in the serum and synovial fluid from different MPS types and species. We also have found for the first time that the inflammation-related advanced glycan endproducts (AGEs) are elevated in MPS serum, as are several proinflammatory sphingolipids and sphingolipid hydrolases. Importantly, in animals treated by either anti-inflammatory therapy or ERT, a reduction of these biomarkers was found. Conclusions: We propose that inflammation-related molecules are useful biomarkers for MPS and other LSD. Several molecules were identified that are abnormally expressed in the different LSD animal models and were corrected after therapy. doi:10.1016/j.ymgme.2012.11.230
217 Eliminating autophagy by nocturnal enteral feeding reverses muscle dysfunction in late-onset Pompe disease Alfred Slonim, Columbia University Medical Center, New York, NY, USA Pompe disease is the only LSD in which skeletal muscle is the primary target. ERT has produced marked improvement of cardiac function, with much less response in skeletal muscle. Over the last 30 years we have demonstrated that high protein & conditioning exercise therapy (HPET) has been beneficial for stabilizing late-onset patients. Recently it has become apparent that autophagic vacuoles play a critically important role, if not the determinant role, in the pathogenesis of skeletal muscle dysfunction. Suppressing autophagy appeared to be necessary to improve muscle function. A genetically induced skeletal muscle autophagydeficient Pompe disease mouse model was generated, which successfully greatly reduced glycogen accumulation, and eliminated autophagic vacuoles. However, this also resulted in dysfunctional mitochondria, muscle atrophy and early demise of these mice (N. Raben, 2012). In order to decrease starvation induced autophagy, nocturnal enteral feeding (NEF) in addition to HPET during the day, was instituted in two male juvenile-onset patients at 4 years and 1 year of age, with resultant near normal muscle function accompanied by clearance of muscle autophagic vacuoles and glycogen (Muscle & Nerve, 2006). Two further juvenile patients have been similarly treated for the last 2 years, and one adultonset patient treated for the last 8 years, with resultant marked functional improvement. The difference in response of autophagy suppression in the KO mouse model and that of the human studies is probably due to autophagy being genetically completely eliminated in the mouse model, while autophagy was not completely eliminated in the adaptive human model. doi:10.1016/j.ymgme.2012.11.231
218 Diaphragm pacing augments ventilatory function in Pompe disease Barbara Smith, Daniel Martin, David Fuller, Lee Ann Lawson, Lawrence Lottenberg, Saleem Islam, Barry Byrne, University of Florida, Gainesville, FL, USA
Pompe disease is an inherited neuromuscular disorder caused by a deficiency of the enzyme acid alpha glucosidase, which is necessary for the degradation of lysosomal glycogen. The clinical presentation is notable for proximal weakness and ventilatory insufficiency, and respiratory morbidity significantly shortens life-expectancy. Intravenous recombinant enzyme-replacement therapy has been developed to treat the muscle pathology presumed to cause hypoventilation. However, we and others have observed evidence of neuropathology in the phrenic motor system of Pompe patients. Here we report the first known implantation of diaphragm pacemakers into patients with Pompe disease, with a goal of reducing dependency on positivepressure ventilation through augmenting phrenic neural output to achieve effective diaphragm contraction. To date, two subjects (ages 53 and 3 years) with continuous ventilator dependence (4 years and 2 months) underwent implantation of chronic pacing electrodes. Four weeks of pre-operative inspiratory muscle strengthening served as a control period and did not yield measurable improvements in unsupported breathing. After implantation of the pacemaker, patients underwent diaphragm conditioning, which consisted of progressive increases in the stimulation parameters, lengthening of daily pacing, and ventilator weaning. By day 65, pacing could support Patient 1 for 12 h of breathing without mechanical ventilation. Patient 2 reached 18 h of ventilator-free, paced breathing by day 30. Both patients adopted deeper inspiratory volumes (33 and 35% increase) with paced breathing. These initial results indicate that diaphragm pacing may offer an adjunctive treatment to existing pharmacological, exercise, and nutritional therapies to maximize independent breathing. doi:10.1016/j.ymgme.2012.11.232
219 Induction of oral tolerance to N-acetylgalactosamine 6-sulfate sulfatase (GALNS) used for enzyme replacement therapy (ERT) in Morquio syndrome type A Angela Sosa-Molanoa,b, Barbara Kariukic, Alan Knutsenc, Clifford Belloned, Shunji Tomatsue, Luis Barreraf, Adriana Montañoe,g, aSaint Louis University, Saint Louis, MO, United States, bPontificia Universidad Javeriana, Bogota, Colombia, cDepartment of Pediatrics, Divisions of Allergy & Immunology Saint Louis University, St Louis, MO, USA, d Department of Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO, USA, eDepartment of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, MO, USA, fInstituto de Errores Innatos del Metabolismo, Pontificia Universidad Javeriana, Bogotá, Colombia, gDepartment of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, USA Mucopolysaccharidosis type IVA (MPS IVA), or Morquio syndrome type A, is an autosomal recessive disorder caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency that results in the intralysosomal accumulation of keratan sulfate and chondroitin-6sulfate. Like other lysosomal storage disorders (LSD), MPS IVA is a good candidate for enzyme replacement therapy (ERT). The immune response against the infused protein in ERT has been reported as the main limitation in the therapeutic effectiveness. Currently, unspecific immunosuppressive protocols have been evaluated for improving ERT efficacy in which the risk–benefit profile is less clear, due to the associated side effects in the patient. The specific induction of tolerance to proteins used in ERT without associated adverse reactions is crucial for the effectiveness of the treatment. In the present study, the main goal is to induce specific tolerance to GALNS in a mouse model by a natural mechanism before its use in ERT. In a previous report, three GALNS peptides were identified as immunogenic regions within the protein. The peptides induced specific cellular responses to GALNS in