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Acid alpha‐glucosidase gene replacement therapy to the diaphragm remodels ventilatory function in severe Pompe disease (1091.8)
Author(s) -
Smith Barbara,
Martin Daniel,
Mah Cathryn,
Lawson Lee Ann,
Falk Darin,
Fuller David,
Islam Saleem,
Collins Shelley,
Byrne Barry
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1091.8
Subject(s) - enzyme replacement therapy , glycogen storage disease type ii , medicine , diaphragm (acoustics) , cardiology , respiratory failure , cardiomyopathy , endocrinology , disease , heart failure , physics , loudspeaker , acoustics
Pompe disease is a neuromuscular disorder due to mutations in the gene that encodes the acid alpha‐glucosidase (GAA) enzyme, which results in lysosomal glycogen accumulation in striated muscle and motor neurons. The severe infantile form leads to cardiac hypertrophy, respiratory failure and early mortality. An approved enzyme replacement therapy reduces the cardiomyopathy and increases survival, yet many patients eventually require mechanical ventilation (MV). Our objective is to investigate an alternative treatment, by correcting the defective gene in an open‐label, Phase I/II clinical study of AAV‐GAA therapy to the diaphragm. We hypothesized that retrograde transport of AAV‐GAA would promote diaphragm glycogen clearance to restore inspiratory motor function. To date, five children (ages 2‐15) with full‐time MV dependence have received intramuscular rAAV1‐CMV‐GAA delivery into the diaphragm and completed follow‐up ventilatory testing. Maximal pressure inspiratory generation did not improve one year after dosing, but maximum unassisted tidal volume increased significantly (median: 22% gain, range: 11‐77%). Moreover, all subjects generated improved spontaneous breathing without MV assistance (median: 586%, range: 192‐2901% improvement over baseline levels). We conclude these findings may be related to vector transduction properties, fiber atrophy from chronic MV, and properties of the postoperative muscle conditioning prescription. Grant Funding Source : K12 HD055929; CRB‐HLBI1‐S‐10‐00223