Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We have used gene targeting to create a mouse model of glycogen storage disease type II, a disease in which distinct clinical phenotypes present at different ages. As in the severe human infantile disease (Pompe Syndrome), mice homozygous for disruption of the acid alpha-glucosidase gene (6(neo)/6(neo)) lack enzyme activity and begin to accumulate glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice have markedly reduced mobility and strength. They grow normally, however, reach adulthood, remain fertile, and, as in the human adult disease, older mice accumulate glycogen in the diaphragm. By 8-9 months of age animals develop obvious muscle wasting and a weak, waddling gait. This model, therefore, recapitulates critical features of both the infantile and the adult forms of the disease at a pace suitable for the evaluation of enzyme or gene replacement. In contrast, in a second model, mutant mice with deletion of exon 6 (Delta6/Delta6), like the recently published acid alpha-glucosidase knockout with disruption of exon 13 (Bijvoet, A. G., van de Kamp, E. H., Kroos, M., Ding, J. H., Yang, B. Z., Visser, P., Bakker, C. E., Verbeet, M. P., Oostra, B. A., Reuser, A. J. J., and van der Ploeg, A. T. (1998) Hum. Mol. Genet. 7, 53-62), have unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathological changes. The genetic background of the mouse strains appears to contribute to the differences among the three models.
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PMID:Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. 966 92

Glycogen storage disease type II (GSD II) is an autosomal recessive disorder caused by defects in the lysosomal acid alpha-glucosidase (GAA) gene. We investigated the feasibility of using a recombinant adenovirus containing the human GAA gene under the control of the cytomegalovirus promoter (AdCMV-GAA) to correct the enzyme deficiency in different cultured cells from patients with the infantile form of GSD II. In GAA-deficient fibroblasts infected with AdCMV-GAA, transduction and transcription of the human transgene resulted in de novo synthesis of GAA protein. The GAA enzyme activity was corrected from the deficient level to 12 times the activity of normal cells. The transduced cells overexpressed the 110 kDa precursor form of GAA, which was secreted into the culture medium and was taken up by recipient cells. The recombinant GAA protein was correctly processed and was active on both an artificial substrate 4-methylumbelliferyl-alpha-D-glucopyranoside (4MUG) and glycogen. In GAA-deficient muscle cells, a significant increase in cellular enzyme level, approximately 20-fold higher than in normal cells, was also observed after viral treatment. The transduced muscle cells were also able to efficiently secrete the recombinant GAA. Moreover, transfer of the human transgene resulted in normalization of cellular glycogen content with clearance of glycogen from lysosomes, as assessed by electron microscopy, in differentiated myotubes. These results demonstrate phenotypic correction of cultured skeletal muscle from a patient with infantile-onset GSD II using a recombinant adenovirus. We conclude that adenovirus-mediated gene transfer might be a suitable model system for further in vivo studies on delivering GAA to GSD II muscle, not only by direct cell targeting but also by a combination of secretion and uptake mechanisms.
Hum Mol Genet 1998 Oct
PMID:Adenovirus-mediated transfer of the acid alpha-glucosidase gene into fibroblasts, myoblasts and myotubes from patients with glycogen storage disease type II leads to high level expression of enzyme and corrects glycogen accumulation. 973 71

Glycogen storage disease type II (GSDII) is caused by lysosomal acid alpha-glucosidase deficiency. Patients have a rapidly fatal or slowly progressive impairment of muscle function. Enzyme replacement therapy is under investigation. For large-scale, cost-effective production of recombinant human acid alpha-glucosidase in the milk of transgenic animals, we have fused the human acid alpha-glucosidase gene to 6.3 kb of the bovine alphaS1-casein gene promoter and have tested the performance of this transgene in mice. The highest production level reached was 2 mg/ml. The major fraction of the purified recombinant enzyme has a molecular mass of 110 kDa and resembles the natural acid alpha-glucosidase precursor from human urine and the recombinant precursor secreted by CHO cells, with respect to pH optimum, Km, Vmax, N-terminal amino acid sequence and glycosylation pattern. The therapeutic potential of the recombinant enzyme produced in milk is demonstrated in vitro and in vivo. The precursor is taken up in a mannose 6-phosphate receptor-dependent manner by cultured fibroblasts, is converted to mature enzyme of 76 kDa and depletes the glycogen deposit in fibroblasts of patients. When injected intravenously, the milk enzyme corrects the acid alpha-glucosidase deficiency in heart and skeletal muscle of GSDII knockout mice.
Hum Mol Genet 1998 Oct
PMID:Recombinant human acid alpha-glucosidase: high level production in mouse milk, biochemical characteristics, correction of enzyme deficiency in GSDII KO mice. 973 85

The lysosome-associated membrane protein (LAMP-1) is elevated in the cells and plasma from lysosomal storage disorder-affected individuals; however, the mechanism of this elevation is not well defined. In this study we have investigated the synthesis, glycoprocessing, trafficking, and turnover of LAMP-1 in human skin fibroblasts from Pompe disease patients and control individuals. There were similar levels of LAMP-1 synthesis in both cell types, but glycoprocessing was retarded in Pompe (T1/2 = 25 min) compared to control (T1/2 = 17 min) fibroblasts. There was also a marked delay in trafficking of LAMP-1 to lysosomes of Pompe (T1/2 = 200 min) compared to control (T1/2 = 100 min) cells. A proportion of newly synthesized LAMP-1 (5.4% in Pompe and 8.5% in controls) was trafficked out of the cell (T1/2 = 3.5 h in controls) and, although significantly smaller than the lysosomal form, still had a transmembrane domain and cytoplasmic tail. In contrast, a soluble lysosomal pool of LAMP-1 had no tail sequence, suggesting that it had been clipped from the membrane. In turnover studies, LAMP-1 was more stable in Pompe (T1/2 = 4.9 days) compared to control (T1/2 = 1. 6 days) cells, implying either reduced proteolysis or lysosomal function, in Pompe cells. These results indicate altered traffic and turnover of LAMP-1 in storage disorders and identify different intracellular and extracellular pools of soluble LAMP-1, suggesting alternative trafficking pathways.
Mol Genet Metab 1999 Mar
PMID:Altered trafficking and turnover of LAMP-1 in Pompe disease-affected cells. 1006 86

We cloned and partially characterized a human endonuclease (Xib) which shows sequence homologies to pancreatic DNase I but an enzymatic activity closer to DNase II. We report on the structural differences found between Xib and other recently cloned human DNases. Fluores cence microscopy analysis of transiently transfected cells with Xib::pEGFP constructs indicate that the protein is located in the cytoplasm and possibly anchored to a membrane, as deduced from a hydrophobic amino acid stretch present at the C-terminal end. Xib is overexpressed in muscle and cardiac tissues and is alternately spliced in several normal and neoplastic cells. In situ hybridization studies using human cardiac and muscle biopsies indicate accumulation of Xib transcript in the vacuoles of muscle cells from patients affected by vacuolar myopathy as acid maltase deficiency; however, no point mutations were detected in their DNA.
Exp Mol Pathol 1999 Jun
PMID:Molecular characterization of a novel endonuclease (Xib) and possible involvement in lysosomal glycogen storage disorders. 1656 3

Pompe's disease or glycogen storage disease type II (GSDII) belongs to the family of inherited lysosomal storage diseases. The underlying deficiency of acid alpha-glucosidase leads in different degrees of severity to glycogen storage in heart, skeletal and smooth muscle. There is currently no treatment for this fatal disease, but the applicability of enzyme replacement therapy is under investigation. For this purpose, recombinant human acid alpha-glucosidase has been produced on an industrial scale in the milk of transgenic rabbits. In this paper we demonstrate the therapeutic effect of this enzyme in our knockout mouse model of GSDII. Full correction of acid alpha-glucosidase deficiency was obtained in all tissues except brain after a single dose of i.v. enzyme administration. Weekly enzyme infusions over a period of 6 months resulted in degradation of lysosomal glycogen in heart, skeletal and smooth muscle. The tissue morphology improved substantially despite the advanced state of disease at the start of treatment. The results have led to the start of a Phase II clinical trial of enzyme replacement therapy in patients.
Hum Mol Genet 1999 Nov
PMID:Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. 1054 93

Glycogen storage disease type II (GSD-II), also known as Pompe disease, is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme. Currently, there is no treatment for this fatal disorder. However, several lines of research suggest the possibility of future treatment. Enzyme replacement strategies hold the greatest hope for patients currently affected by GSD-II, but future strategies could include in vivo or ex vivo gene therapy approaches and/or mesenchymal stem cell or bone-marrow transplantation approaches. Each of the approaches might eventually be combined to further improve the overall clinical efficacy of any one treatment regimen. The lessons learned from GSD-II research will also benefit a great number of individuals affected by other genetic disorders.
Mol Med Today 2000 Jun
PMID:Towards a molecular therapy for glycogen storage disease type II (Pompe disease). 1084 Mar 83

Pompe disease is a generalized lysosomal glycogenosis affecting essentially the skeletal muscles and the heart. It is due to the deficiency of acid alpha-glucosidase, also called acid maltase, involved in glycogen degradation by the cleavage of alpha-1,4 and alpha-1,6 glycosidic linkages. The severe infantile, milder juvenile, and late-onset or adult forms are associated under the generic name of glycogenoses type II. The clinical picture can differ according to these variants, forming a clinical spectrum from cardiorespiratory failure with early death in the infantile variant to late muscular weakness or respiratory problems in the adult variant. Enzymatic pre- and postnatal diagnoses and mutation characterization are available. Different therapeutic attempts have been conceived and some of them have come to clinical trials. Several pilot studies have demonstrated the feasibility of gene therapy and remarkable advances have been realized. Of particular interest, strategies for gene therapy in a generalized disease like Pompe disease must be accompanied by the secretion and uptake of the corrective enzyme by more distant cells or tissues in order to obtain efficient results. Preliminary positive results have been obtained in animal models, and new approaches with improvements in the access to muscle and heart, in the efficacy and innocuity of vectors, and in the clinical evolution are proposed. Gene therapy is a promising strategy for Pompe disease. However, several steps must be explored before this method becomes clinically successful.
Mol Genet Metab 2000 Jul
PMID:Approach to gene therapy of glycogenosis type II (Pompe disease). 1092 70

Both enzyme replacement and gene therapy of lysosomal storage disorders rely on the receptor-mediated uptake of lysosomal enzymes secreted by cells, and for each lysosomal disorder it is necessary to select the correct cell type for recombinant enzyme production or for targeting gene therapy. For example, for the therapy of Pompe disease, a severe metabolic myopathy and cardiomyopathy caused by deficiency of acid alpha-glucosidase (GAA), skeletal muscle seems an obvious choice as a depot organ for local therapy and for the delivery of the recombinant enzyme into the systemic circulation. Using knockout mice with this disease and transgenes containing cDNA for the human enzyme under muscle or liver specific promoters controlled by tetracycline, we have demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising <5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110 kDa precursor form. Furthermore, using tetracycline regulation, we somatically induced human GAA in the knockout mice, and demonstrated that the skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.
Hum Mol Genet 2001 Sep 15
PMID:Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy. 1159 Jan 21

Glycogenosis type II (GSDII, Pompe disease) is an autosomal recessive lysosomal storage disease caused by a deficiency of acid alpha-glucosidase (acid maltase, GAA). The enzyme degrades alpha -1,4 and alpha -1,6 linkages in glycogen, maltose, and isomaltose. Deficiency of the enzyme results in accumulation of glycogen within lysosomes and in cytoplasm eventually leading to tissue destruction. The discovery of the acid a-glucosidase gene has led to rapid progress in understanding the molecular basis of glycogenosis type II and the biological properties of the GAA protein. The last decade has seen several developments: 1) extensive mutational analysis in patients with different forms of the disease, 2) characterization of the enzyme biosynthesis, processing, and lysosomal targeting, 3) generation of knockout mouse models, 4) development of viral vectors for gene replacement therapy, 5) the production of recombinant human enzyme, and 6) a shift in the enzyme replacement therapy approach from theory to practice. It is anticipated that the enzyme replacement therapy will be widely available for human use in the near future. Several recent reviews (including the most comprehensive one by R. Hirschhorn and A. Reuser [1]), address clinical, biochemical and genetic aspects of the disease, as well as development of new therapies for GSDII [2, 3, 4]. In this article we will review recent findings in the area including rapidly accumulating molecular genetic data (more than 20 mutations need to be added to the list), transcriptional control of gene expression, studies in mouse models, and new approaches to gene therapy. We will also highlight some emerging questions following the introduction of enzyme replacement therapy.
Curr Mol Med 2002 Mar
PMID:Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). 1194 32


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