CLINICAL AND METABOLIC CORRECTION OF POMPE-DISEASE BY ENZYME THERAPY IN ACID MALTASE-DEFICIENT QUAIL

Pompe disease is a fatal genetic muscle disorder caused by a deficienc y of acid a-glucosidase (GAA), a glycogen degrading lysosomal enzyme, GAA-deficient (AMD) Japanese quails exhibit progressive myopathy and c annot lift their wings, fly, or right themselves from the supine posit ion (flip test). Six 4-wk-old acid maltase-deficient quails, with the clinical symptoms listed, were intravenously injected with 14 or 4.2 m g/kg of precursor form of recombinant human GAA or buffer alone every 2-3 d for 18 d (seven injections), On day 18, both high dose-treated b irds (14 mg/kg) scored positive flip tests and flapped their wings, an d one bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules, In sh arp contrast, sham-treated quail muscle had markedly increased glycoge n granules, multi-vesicular autophagosomes, and inter-and intrafascicu lar fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved l ess biochemically and histopathologically than high dose birds, indica ting a dose-dependent response. Additional experiment with intermediat e doses and extended treatment (four birds, 5.7-9 mg/kg for 45 d) halt ed the progression of the disease. Our data is the first to show that an exogenous protein can target to muscle and produce muscle improveme nt, These data also suggest enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.