title: Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity.
abstract: Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid α-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1-CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.
authors.affiliation: Department of Physical Therapy, P.O. Box 100154, University of Florida, Gainesville, FL 32610, United States; Department of Pediatrics, P.O. Box 100144, University of Florida, Gainesville, FL 32610, United States. Electronic address: bksmith@phhp.ufl.edu.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Department of Physical Therapy, P.O. Box 100154, University of Florida, Gainesville, FL 32610, United States.
authors.forename: A Daniel
authors.initials: AD
authors.lastname: Martin
authors.affiliation: Department of Pediatrics, P.O. Box 100144, University of Florida, Gainesville, FL 32610, United States.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Lawson
authors.affiliation: College of Liberal Arts and Sciences, P.O. Box 117300, University of Florida, Gainesville, FL 32611, United States.
authors.forename: Valerie
authors.initials: V
authors.lastname: Vernot
authors.affiliation: College of Public Health and Health Professions, P.O. Box 100185, University of Florida, Gainesville, FL 21610, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Marcus
authors.affiliation: Department of Surgery, P.O. Box 100296, University of Florida, Gainesville, FL 32610, United States.
authors.forename: Saleem
authors.initials: S
authors.lastname: Islam
authors.affiliation: Department of Pediatrics Critical Care Division, University of Tennessee Health Science Center, 50 N. Dunlap, Memphis, TN 38103, United States.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Shafi
authors.affiliation: Department of Pediatrics, P.O. Box 100144, University of Florida, Gainesville, FL 32610, United States.
authors.forename: Manuela
authors.initials: M
authors.lastname: Corti
authors.affiliation: Department of Pediatrics, P.O. Box 100144, University of Florida, Gainesville, FL 32610, United States.
authors.forename: Shelley W
authors.initials: SW
authors.lastname: Collins
authors.affiliation: Department of Pediatrics, P.O. Box 100144, University of Florida, Gainesville, FL 32610, United States.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003964:Diaphragm / Q000502:physiology*; D004576:Electromyography; D005081:Exercise Therapy; D005260:Female; D015316:Genetic Therapy; D006009:Glycogen Storage Disease Type II / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000503:physiopathology; D011446:Prospective Studies; D012131:Respiratory Insufficiency / Q000000981:diagnostic imaging / Q000209:etiology* / Q000628:therapy*; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000235:genetics / Q000627:therapeutic use
chemical_list: D000520:alpha-Glucosidases
keywords: Diaphragm; Gene therapy; Pompe disease; Ventilatory insufficiency