Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail.

Abstract

Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase (GAA), a glycogen degrading lysosomal enzyme. GAA-deficient (AMD) Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position (flip test). Six 4-wk-old acid maltase-deficient quails, with the clinical symptoms listed, were intravenously injected with 14 or 4.2 mg/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 birds (14 mg/kg) scored positive flip tests and flapped their wings, and 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 sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multi-vesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiment with intermediate doses and extended treatment (four birds, 5.7-9 mg/kg for 45 d) halted the progression of the disease. Our data is the first to show that an exogenous protein can target to muscle and produce muscle improvement. These data also suggest enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.

Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model

“…10 Long-term correction of GSD-II in GAA-KO/SCID mice F Xu et al GSD-II patients. 15,20 Recently, it has been demonstrated that restoration of a single muscle's contractile force can be achieved after intramuscular injection of an AAV vector encoding hGAA. 21 However, the evaluation of overall gross muscle strength has not been reported after attempting gene therapy using viral vectors in GSD-II animal models.…”

Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling

“…2 The prospect of enzyme therapy for GSD II highlights the immediate need for accurate figures on the frequency of the disease. 3,4 The figure of 1 in 100 000 normally quoted is not based on solid data. 1,5 Given present knowledge of the molecular genetics of GSD II, 1,2,6 and the genotype-phenotype correlation, 7,8 we now have the tools to update the meagre and aging data on the frequency of the disease.…”

Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

“…Clinical trials of ERT in MPS type VI patients are in progress (23). ERT in quails with acid-␣-glucosidase deficiency (glycogenosis type II) improved muscle function (25). In four infants with Pompe's disease, ERT resulted in improved cardiac structure and function and prolonged survival (26)(27)(28), but long-term results are not yet available.…”