Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity

• Published in: Experimental neurology Vol. 287; no. Pt 2; pp. 216 - 224
• Main Authors: Smith, Barbara K., Martin, A. Daniel, Lawson, Lee Ann, Vernot, Valerie, Marcus, Jordan, Islam, Saleem, Shafi, Nadeem, Corti, Manuela, Collins, Shelley W., Byrne, Barry J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Adolescent; alpha-Glucosidases - genetics; alpha-Glucosidases - therapeutic use; Child; Child, Preschool; Diaphragm; Diaphragm - physiology; Electromyography; Exercise Therapy; Female; Gene therapy; Genetic Therapy; Glycogen Storage Disease Type II - complications; Glycogen Storage Disease Type II - diagnostic imaging; Glycogen Storage Disease Type II - genetics; Glycogen Storage Disease Type II - therapy; Humans; Magnetic Resonance Imaging; Male; Muscle, Skeletal - physiopathology; Pompe disease; Prospective Studies; Respiratory Insufficiency - diagnostic imaging; Respiratory Insufficiency - etiology; Respiratory Insufficiency - therapy; Treatment Outcome; Ventilatory insufficiency; Pompe disease; MIP; MRI; Ventilatory insufficiency; ERT; GAA; IMST; LC; MV; Diaphragm; Gene therapy
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2016.07.013

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. •Children with Pompe disease and ventilatory insufficiency received AAV1-CMG-GAA.•Exercise alone did not change respiratory muscle function in any subjects.•In less-affected children, dynamic respiratory function improved after gene therapy.