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Nina Raben - One of the best experts on this subject based on the ideXlab platform.
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intravenous injection of an aav php b vector encoding human Acid α glucosidase rescues both muscle and cns defects in murine pompe disease
Molecular therapy. Methods & clinical development, 2019Co-Authors: Jeong-a Lim, Priya S Kishnani, Nina Raben, Fengqin Gao, Baodong SunAbstract:Pompe disease, a severe and often fatal neuromuscular disorder, is caused by a deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA). The disease is characterized by the accumulation of excess glycogen in the heart, skeletal muscle, and CNS. Currently approved enzyme replacement therapy or experimental adeno-associated virus (AAV)-mediated gene therapy has little effect on CNS correction. Here we demonstrate that a newly developed AAV-PHP.B vector can robustly transduce both the CNS and skeletal muscles in GAA-knockout (GAAKO) mice. A single intravenous injection of an AAV-PHP.B vector expressing human GAA under the control of cytomegalovirus (CMV) enhancer-chicken β-actin (CB) promoter into 2-week-old GAAKO mice resulted in widespread GAA expression in the affected tissues. Glycogen contents were reduced to wild-type levels in the brain and heart, and they were significantly decreased in skeletal muscle by the AAV treatment. The histological assay showed no visible glycogen in any region of the brain and spinal cord of AAV-treated mice. In this study, we describe a set of behavioral tests that can detect early neurological deficits linked to extensive lysosomal glycogen accumulation in the CNS of untreated GAAKO mice. Furthermore, we demonstrate that the therapy can help prevent the development of these abnormalities.
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Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease
Elsevier, 2019Co-Authors: Jeong-a Lim, Priya S Kishnani, Nina Raben, Fengqin Gao, Baodong SunAbstract:Pompe disease, a severe and often fatal neuromuscular disorder, is caused by a deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA). The disease is characterized by the accumulation of excess glycogen in the heart, skeletal muscle, and CNS. Currently approved enzyme replacement therapy or experimental adeno-associated virus (AAV)-mediated gene therapy has little effect on CNS correction. Here we demonstrate that a newly developed AAV-PHP.B vector can robustly transduce both the CNS and skeletal muscles in GAA-knockout (GAAKO) mice. A single intravenous injection of an AAV-PHP.B vector expressing human GAA under the control of cytomegalovirus (CMV) enhancer-chicken β-actin (CB) promoter into 2-week-old GAAKO mice resulted in widespread GAA expression in the affected tissues. Glycogen contents were reduced to wild-type levels in the brain and heart, and they were significantly decreased in skeletal muscle by the AAV treatment. The histological assay showed no visible glycogen in any region of the brain and spinal cord of AAV-treated mice. In this study, we describe a set of behavioral tests that can detect early neurological deficits linked to extensive lysosomal glycogen accumulation in the CNS of untreated GAAKO mice. Furthermore, we demonstrate that the therapy can help prevent the development of these abnormalities. Keywords: Pompe disease, Acid Alpha-Glucosidase deficiency, gene therapy, AAV-PHP.B vector, glycogen storage, CNS, neurological deficit
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the value of muscle biopsies in pompe disease identifying lipofuscin inclusions in juvenile and adult onset patients
Acta neuropathologica communications, 2014Co-Authors: Erin J Feeney, Priya S Kishnani, Benedikt Schoser, Yinhsiu Chien, Sean N Prater, Hanna Mandel, Stephanie Austin, Wuhliang Hwu, Evelyn Ralston, Nina RabenAbstract:Background Pompe disease, an inherited deficiency of lysosomal Acid Alpha-Glucosidase (GAA), is a metabolic myopathy with heterogeneous clinical presentations. Late-onset Pompe disease (LOPD) is a debilitating progressive muscle disorder that can occur anytime from early childhood to late adulthood. Enzyme replacement therapy (ERT) with recombinant human GAA is currently available for Pompe patients. Although ERT shows some benefits, the reversal of skeletal muscle pathology - lysosomal glycogen accumulation and autophagic buildup - remains a challenge. In this study, we examined the clinical status and muscle pathology of 22 LOPD patients and one atypical infantile patient on ERT to understand the reasons for muscle resistance to ERT.
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skeletal muscle pathology of infantile pompe disease during long term enzyme replacement therapy
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sean N Prater, Erin J Feeney, Nina Raben, Trusha Patel, Anne F Buckley, Hanna Mandel, Eugene Vlodavski, Suhrad G Banugaria, Priya S KishnaniAbstract:Background Pompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD).
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suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder murine pompe disease
Autophagy, 2010Co-Authors: Nina Raben, Kanneboyina Nagaraju, Shoichi Takikita, Rebecca Baum, Cynthia Schreiner, Tao Xie, Rachel Myerowitz, Masaaki Komatsu, Jack H Van Der Meulen, Evelyn RalstonAbstract:Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which Acid Alpha-Glucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50–60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy.
Priya S Kishnani - One of the best experts on this subject based on the ideXlab platform.
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intravenous injection of an aav php b vector encoding human Acid α glucosidase rescues both muscle and cns defects in murine pompe disease
Molecular therapy. Methods & clinical development, 2019Co-Authors: Jeong-a Lim, Priya S Kishnani, Nina Raben, Fengqin Gao, Baodong SunAbstract:Pompe disease, a severe and often fatal neuromuscular disorder, is caused by a deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA). The disease is characterized by the accumulation of excess glycogen in the heart, skeletal muscle, and CNS. Currently approved enzyme replacement therapy or experimental adeno-associated virus (AAV)-mediated gene therapy has little effect on CNS correction. Here we demonstrate that a newly developed AAV-PHP.B vector can robustly transduce both the CNS and skeletal muscles in GAA-knockout (GAAKO) mice. A single intravenous injection of an AAV-PHP.B vector expressing human GAA under the control of cytomegalovirus (CMV) enhancer-chicken β-actin (CB) promoter into 2-week-old GAAKO mice resulted in widespread GAA expression in the affected tissues. Glycogen contents were reduced to wild-type levels in the brain and heart, and they were significantly decreased in skeletal muscle by the AAV treatment. The histological assay showed no visible glycogen in any region of the brain and spinal cord of AAV-treated mice. In this study, we describe a set of behavioral tests that can detect early neurological deficits linked to extensive lysosomal glycogen accumulation in the CNS of untreated GAAKO mice. Furthermore, we demonstrate that the therapy can help prevent the development of these abnormalities.
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Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease
Elsevier, 2019Co-Authors: Jeong-a Lim, Priya S Kishnani, Nina Raben, Fengqin Gao, Baodong SunAbstract:Pompe disease, a severe and often fatal neuromuscular disorder, is caused by a deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA). The disease is characterized by the accumulation of excess glycogen in the heart, skeletal muscle, and CNS. Currently approved enzyme replacement therapy or experimental adeno-associated virus (AAV)-mediated gene therapy has little effect on CNS correction. Here we demonstrate that a newly developed AAV-PHP.B vector can robustly transduce both the CNS and skeletal muscles in GAA-knockout (GAAKO) mice. A single intravenous injection of an AAV-PHP.B vector expressing human GAA under the control of cytomegalovirus (CMV) enhancer-chicken β-actin (CB) promoter into 2-week-old GAAKO mice resulted in widespread GAA expression in the affected tissues. Glycogen contents were reduced to wild-type levels in the brain and heart, and they were significantly decreased in skeletal muscle by the AAV treatment. The histological assay showed no visible glycogen in any region of the brain and spinal cord of AAV-treated mice. In this study, we describe a set of behavioral tests that can detect early neurological deficits linked to extensive lysosomal glycogen accumulation in the CNS of untreated GAAKO mice. Furthermore, we demonstrate that the therapy can help prevent the development of these abnormalities. Keywords: Pompe disease, Acid Alpha-Glucosidase deficiency, gene therapy, AAV-PHP.B vector, glycogen storage, CNS, neurological deficit
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the value of muscle biopsies in pompe disease identifying lipofuscin inclusions in juvenile and adult onset patients
Acta neuropathologica communications, 2014Co-Authors: Erin J Feeney, Priya S Kishnani, Benedikt Schoser, Yinhsiu Chien, Sean N Prater, Hanna Mandel, Stephanie Austin, Wuhliang Hwu, Evelyn Ralston, Nina RabenAbstract:Background Pompe disease, an inherited deficiency of lysosomal Acid Alpha-Glucosidase (GAA), is a metabolic myopathy with heterogeneous clinical presentations. Late-onset Pompe disease (LOPD) is a debilitating progressive muscle disorder that can occur anytime from early childhood to late adulthood. Enzyme replacement therapy (ERT) with recombinant human GAA is currently available for Pompe patients. Although ERT shows some benefits, the reversal of skeletal muscle pathology - lysosomal glycogen accumulation and autophagic buildup - remains a challenge. In this study, we examined the clinical status and muscle pathology of 22 LOPD patients and one atypical infantile patient on ERT to understand the reasons for muscle resistance to ERT.
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skeletal muscle pathology of infantile pompe disease during long term enzyme replacement therapy
Orphanet Journal of Rare Diseases, 2013Co-Authors: Sean N Prater, Erin J Feeney, Nina Raben, Trusha Patel, Anne F Buckley, Hanna Mandel, Eugene Vlodavski, Suhrad G Banugaria, Priya S KishnaniAbstract:Background Pompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD).
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a randomized study of alglucosidase alfa in late onset pompe s disease
The New England Journal of Medicine, 2010Co-Authors: Ans T Van Der Ploeg, Priya S Kishnani, Paula R. Clemens, Pascal Laforêt, Deyanira Corzo, Diana M Escolar, Julaine Florence, Geert Jan Groeneveld, Serge Herson, Stephen LakeAbstract:Background Pompe’s disease is a metabolic myopathy caused by a deficiency of Acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe’s disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe’s disease. Methods Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). Results At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1±13.1 m on the 6-minute walk test and an absolute increase of 3.4±1.2 percentage points in FVC; P = 0.03 and P = 0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). Conclusions In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)
Paul H Plotz - One of the best experts on this subject based on the ideXlab platform.
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suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in pompe disease
Human Molecular Genetics, 2008Co-Authors: Nina Raben, Victoria K Hill, Shoichi Takikita, Evelyn Ralston, Lauren Shea, Rebecca Baum, Noboru Mizushima, Paul H PlotzAbstract:The role of autophagy, a catabolic lysosome-dependent pathway, has recently been recognized in a variety of disorders, including Pompe disease, the genetic deficiency of the glycogen-degrading lysosomal enzyme Acid-alpha glucosidase. Accumulation of lysosomal glycogen, presumably transported from the cytoplasm by the autophagic pathway, occurs in multiple tissues, but pathology is most severe in skeletal and cardiac muscle. Skeletal muscle pathology also involves massive autophagic buildup in the core of myofibers. To determine if glycogen reaches the lysosome via autophagy and to ascertain whether autophagic buildup in Pompe disease is a consequence of induction of autophagy and/or reduced turnover due to defective fusion with lysosomes, we generated muscle-specific autophagy-deficient Pompe mice. We have demonstrated that autophagy is not required for glycogen transport to lysosomes in skeletal muscle. We have also found that Pompe disease involves induction of autophagy but manifests as a functional deficiency of autophagy because of impaired autophagosomal-lysosomal fusion. As a result, autophagic substrates, including potentially toxic aggregate-prone ubiquitinated proteins, accumulate in Pompe myofibers and may cause profound muscle damage.
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induction of tolerance to a recombinant human enzyme Acid alpha glucosidase in enzyme deficient knockout mice
Transgenic Research, 2003Co-Authors: Nina Raben, John J Hopwood, Kanneboyina Nagaraju, Alicia Lee, Yesenia Rivera, Tejas Jatkar, Paul H PlotzAbstract:When knockout mice are used to test the efficacy of recombinant human proteins, the animals often develop antibodies to the enzyme, precluding long-term pre-clinical studies. This has been a problem with a number of models, for example, the evaluation of gene or enzyme replacement therapies in a knockout model of glycogen storage disease type II (GSDII; Pompe syndrome). In this disease, the lack of Acid Alpha-Glucosidase (GAA) results in lysosomal accumulation of glycogen, particularly in skeletal and cardiac muscle. Here, we report that in a GAA-deficient mouse model of GSDII, low levels of transgene-encoded human GAA expressed in skeletal muscle or liver dramatically blunt or abolish the immune response to human recombinant protein. Of two low expression transgenic lines, only the liver-expressing line exhibited a profound GAA deficiency in skeletal muscle and heart indistinguishable from that in the original knockouts. The study suggests that the induction of tolerance in animal models of protein deficiencies could be achieved by restricting the expression of a gene of interest to a particular, carefully chosen tissue.
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glycogen stored in skeletal but not in cardiac muscle in Acid α glucosidase mutant pompe mice is highly resistant to transgene encoded human enzyme
Molecular Therapy, 2002Co-Authors: Nina Raben, Kanneboyina Nagaraju, Alicia Lee, Tejas Jatkar, Sunita Dwivedi, Paul H PlotzAbstract:Although many lysosomal disorders are corrected by a small amount of the missing enzyme, it has been generally accepted that 20-30% of normal Acid Alpha-Glucosidase (GAA) activity, provided by gene or enzyme replacement therapy, would be required to reverse the myopathy and cardiomyopathy in Pompe disease. We have addressed the issue of reversibility of the disease in the Gaa(-/-) mouse model. We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system. We have demonstrated that levels of 20-30% of normal activity are indeed sufficient to clear glycogen in the heart of young Gaa(-/-) mice, but not in older mice with a considerably higher glycogen load. However, in skeletal muscle-a major organ affected in infantile and in milder, late-onset variants in humans-induction of GAA expression in young Gaa(-/-) mice to levels greatly exceeding wildtype values did not result in full phenotypic correction, and some muscle fibers showed little or no glycogen clearance. The results demonstrate that complete reversal of pathology in skeletal muscle or long-affected heart muscle will require much more enzyme than previously expected or a different approach.
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correction of glycogen storage disease type ii by enzyme replacement with a recombinant human Acid maltase produced by over expression in a cho dhfr neg cell line
Biochemical and Biophysical Research Communications, 2000Co-Authors: Frank Martiniuk, Nina Raben, Agnes Chen, Vincent Donnabella, Eleni Arvanitopoulos, Alfred E Slonim, Paul H PlotzAbstract:Abstract Inherited genetic deficiency of lysosomal Acid alpha glucosidase or Acid maltase (GAA) results in the autosomal recessive glycogen storage disease type II (GSD II). To investigate whether we could generate a functional recombinant human GAA (rhGAA) for enzyme replacement therapy, we subcloned the cDNAs for human GAA and mouse dihydrofolate reductase (DHFR) into DHFRneg Chinese hamster ovary cells and established a stable cotransformant that expressed rhGAA. We cultured the recombinant cells in media with progressively increasing concentrations of methotrexate and found that human GAA enzyme activity increased to over 2,000 IU per gram protein. Importantly, the human GAA enzyme activity correlated to equivalent amounts of human GAA protein by rocketimmunoelectrophoresis. We confirmed that the human GAA enzyme activity corresponded to an amplification in human GAA mRNA by Northern analysis and human GAA cDNA copy number by Southern analysis. Exposing the rhGAA to human GSDII fibroblast cells or patient's lymphocytes or monocytes resulted in uptake of the rhGAA and reversal of the enzymatic defect. Mannose-6-phosphate in the media blocked uptake. GAA −/− mice were treated with the rhGAA at 1 mg/kg, which resulted in heterozygous levels of GAA in tissues, most notably skeletal muscle, heart and diaphragm after two infusions. More importantly, after multiple infusions, hind, and fore-limb muscle weakness was reversed. This rhGAA would be ideal for enzyme replacement therapy in GSD II.
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leaky splicing mutation in the Acid maltase gene is associated with delayed onset of glycogenosis type ii
American Journal of Human Genetics, 1995Co-Authors: Cornelius F Boerkoel, Paul H Plotz, R Exelbert, C Nicastri, Ralph C Nichols, Frederick W Miller, Nina RabenAbstract:An autosomal recessive deficiency of Acid {alpha}-glucosidase (GAA), type II glycogenosis, is genetically and clinically heterogeneous. The discovery of an enzyme-inactivating genomic deletion of exon 18 in three unrelated genetic compound patients - two infants and and adult - provided a rare opportunity to analyze the effect of the second mutation in patients who displayed dramatically different phenotypes. A deletion of Lys-903 in one patient and a substitution of Arg for Leu-299 in another resulted in the fatal infantile form. In the adult, a T-to-G base change at position-13 of intron 1 resulted in alternatively spliced transcripts with deletion of exon 2, the location of the start codon. The low level of active enzyme (12% of normal) generated from the leakage of normally spliced mRNA sustained the patient to adult life. 61 refs., 9 figs., 3 tabs.
Marian A Kroos - One of the best experts on this subject based on the ideXlab platform.
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high frequency of Acid α glucosidase pseudodeficiency complicates newborn screening for glycogen storage disease type ii in the japanese population
Molecular Genetics and Metabolism, 2009Co-Authors: Shingo Kumamoto, Marian A Kroos, Arnold J J Reuser, Tatsuya Katafuchi, Kimitoshi Nakamura, Fumio Endo, Eri Oda, Torayuki Okuyama, Toshika OkumiyaAbstract:To investigate the feasibility of newborn screening for glycogen storage disease type II (GSDII; Pompe disease or Acid maltase deficiency) in the Japanese population, we assayed the Acid Alpha-Glucosidase activity in dried blood spots from 715 Japanese newborns and 18 previously diagnosed patients using a fluorometric procedure. The enzyme activity of apparently healthy newborns showed a bimodal distribution. The median activity of the minor group (31 individuals, 4.3% of the samples) was 6.5 times lower than that of the major group. Four of the 715 control samples (0.56%) fell in the patient range. We then analyzed genomic DNA, extracted from the same blood spots, for the occurrence of two sequence variants, c.1726G>A and c.2065G>A, known to cause "pseudodeficiency". This analysis revealed that 27 of 28 individuals homozygous for c.[1726A; 2065A] belonged to the minor group. One c.[1726A; 2065A] homozygote had just slightly higher activity. Twelve of the 18 patients with GSDII either had one (9 cases) or two (3 cases) c.[1726A; 2065A] alleles. The frequency of this allele was double in the patient compared to the control group (0.42 vs 0.19) at the expense of a lower frequency of the c.[1726G; 2065G] and c.[1726G; 2065A] alleles (0.58 vs 0.71 and 0 vs 0.1). These findings illustrate that c.[1726A; 2065A] homozygosity among apparently healthy individuals (3.9 per 100) complicates newborn screening for GSDII in Japan, and further that one or more pathogenic mutations are associated with the c.[1726A; 2065A] allele.
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structural modeling of mutant α glucosidases resulting in a processing transport defect in pompe disease
Journal of Human Genetics, 2009Co-Authors: Kanako Sugawara, Marian A Kroos, Arnold J J Reuser, Seiji Saito, Masakazu Sekijima, Kazuki Ohno, Youichi Tajima, Hitoshi SakurabaAbstract:To elucidate the mechanism underlying transport and processing defects from the viewpoint of enzyme folding, we constructed three-dimensional models of human Acid Alpha-Glucosidase encompassing 27 relevant amino Acid substitutions by means of homology modeling. Then, we determined in each separate case the number of affected atoms, the root-mean-square distance value and the solvent-accessible surface area value. The analysis revealed that the amino Acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the Acid Alpha-Glucosidase. They were distributed from the core to the surface of the enzyme molecule, and the predicted structural changes varied from large to very small. Among the structural changes, we paid particular attention to G377R and G483R. These two substitutions are predicted to cause electrostatic changes in neighboring small regions on the molecular surface. The quality control system of the endoplasmic reticulum apparently detects these very small structural changes and degrades the mutant enzyme precursor (G377R), but also the cellular sorting system might be misled by these minor changes whereby the precursor is secreted instead of being transported to lysosomes (G483R).
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update of the pompe disease mutation database with 107 sequence variants and a format for severity rating
Human Mutation, 2008Co-Authors: Marian A Kroos, Laura Van Vliet, Robert J Pomponio, Rachel Palmer, Michael Phipps, Robert Van Der Helm, Dicky J J Halley, Arnold J J ReuserAbstract:Pompe disease was named after the Dutch pathologist Dr JC Pompe who reported about a deceased infant with idiopathic hypertrophy of the heart. The clinical findings were failure to thrive, generalized muscle weakness and cardio-respiratory failure. The key pathologic finding was massive storage of glycogen in heart, skeletal muscle and many other tissues. The disease was classified as glycogen storage disease type II and decades later shown to be a lysosomal disorder caused by Acid Alpha-Glucosidase deficiency. The clinical spectrum of Pompe disease appeared much broader than originally recognized. Adults with the same enzyme deficiency, alternatively named Acid maltase deficiency, were reported to have slowly progressive skeletal muscle weakness and respiratory problems, but no cardiac involvement. The clinical heterogeneity is largely explained by the kind and severity of mutations in the Acid Alpha-Glucosidase gene (GAA), but secondary factors, as yet unknown, have a substantial impact. The Pompe disease mutation database aims to list all GAA sequence variations and describe their effect. This update with 107 sequence variations (95 being novel) brings the number of published variations to 289, the number of non-pathogenic mutations to 67 and the number of proven pathogenic mutations to 197. Further, this article introduces a tool to rate the various mutations by severity, which will improve understanding of the genotype-phenotype correlation and facilitate the diagnosis and prognosis in Pompe disease.
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chemical chaperones improve transport and enhance stability of mutant α glucosidases in glycogen storage disease type ii
Molecular Genetics and Metabolism, 2007Co-Authors: Toshika Okumiya, Marian A Kroos, Laura Van Vliet, Hiroaki Takeuchi, Ans T Van Der Ploeg, Arnold J J ReuserAbstract:Glycogen storage disease type II (GSDII; Pompe disease or Acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal Acid Alpha-Glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness. Defects in post-translational modification and transport of mutant AalphaGlu species are frequently encountered and may potentially be corrected with chaperone-mediated therapy. In the present study, we have tested this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones to correct the AalphaGlu deficiency in cultured fibroblasts from patients with GSDII. Four mutant phenotypes were chosen: Y455F/Y455F, P545L/P545L, 525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L, N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and activity of AalphaGlu in a dose dependent manner, while it had no effect on the reference enzyme beta-hexosaminidase. NB-DNJ promoted export from the endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of mutant AalphaGlu species, Y455F and P545L, inside the lysosomes. In long-term culture, the AalphaGlu activity in the fibroblasts from the patients with mutant phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold, respectively, in the presence of 10mumol/L NB-DNJ. However, the effect of NB-DNJ on Y455F/Y455F subsided quickly after removal of the compound. We conclude that NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms of AalphaGlu that are trapped in the ER, poorly transported or labile in the lysosomal environment. Chemical chaperone therapy could create new perspectives for therapeutic intervention in GSDII.
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twenty two novel mutations in the lysosomal α glucosidase gene gaa underscore the genotype phenotype correlation in glycogen storage disease type ii
Human Mutation, 2004Co-Authors: M M P Hermans, Marian A Kroos, Ans T Van Der Ploeg, Hitoshi Sakuraba, Dik Van Leenen, Clare E Beesley, Ron A Wevers, W J Kleijer, Helen Michelakakis, Edwin P KirkAbstract:Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to Acid Alpha-Glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the Acid Alpha-Glucosidase gene (GAA) encoding Acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on Acid Alpha-Glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.
Ans T Van Der Ploeg - One of the best experts on this subject based on the ideXlab platform.
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Satellite cells maintain regenerative capacity but fail to repair disease-associated muscle damage in mice with Pompe disease
BMC, 2018Co-Authors: Gerben J. Schaaf, Monica Cardone, Giancarlo Parenti, Ans T Van Der Ploeg, Tom J. M. Van Gestel, Stijn In ‘t L. M. Groen, Bart De Jong, Björn Boomaars, Antonietta Tarallo, W. Pim W. M. PijnappelAbstract:Abstract Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme Acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa −/− satellite cells to regenerate muscle damage. Gaa −/− mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa −/− muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa −/− mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa −/− animals. Surprisingly, both young and old Gaa −/− mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa −/− mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa −/− mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa −/− mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa −/− satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease
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a randomized study of alglucosidase alfa in late onset pompe s disease
The New England Journal of Medicine, 2010Co-Authors: Ans T Van Der Ploeg, Priya S Kishnani, Paula R. Clemens, Pascal Laforêt, Deyanira Corzo, Diana M Escolar, Julaine Florence, Geert Jan Groeneveld, Serge Herson, Stephen LakeAbstract:Background Pompe’s disease is a metabolic myopathy caused by a deficiency of Acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe’s disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe’s disease. Methods Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). Results At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1±13.1 m on the 6-minute walk test and an absolute increase of 3.4±1.2 percentage points in FVC; P = 0.03 and P = 0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). Conclusions In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)
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chemical chaperones improve transport and enhance stability of mutant α glucosidases in glycogen storage disease type ii
Molecular Genetics and Metabolism, 2007Co-Authors: Toshika Okumiya, Marian A Kroos, Laura Van Vliet, Hiroaki Takeuchi, Ans T Van Der Ploeg, Arnold J J ReuserAbstract:Glycogen storage disease type II (GSDII; Pompe disease or Acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal Acid Alpha-Glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness. Defects in post-translational modification and transport of mutant AalphaGlu species are frequently encountered and may potentially be corrected with chaperone-mediated therapy. In the present study, we have tested this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones to correct the AalphaGlu deficiency in cultured fibroblasts from patients with GSDII. Four mutant phenotypes were chosen: Y455F/Y455F, P545L/P545L, 525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L, N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and activity of AalphaGlu in a dose dependent manner, while it had no effect on the reference enzyme beta-hexosaminidase. NB-DNJ promoted export from the endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of mutant AalphaGlu species, Y455F and P545L, inside the lysosomes. In long-term culture, the AalphaGlu activity in the fibroblasts from the patients with mutant phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold, respectively, in the presence of 10mumol/L NB-DNJ. However, the effect of NB-DNJ on Y455F/Y455F subsided quickly after removal of the compound. We conclude that NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms of AalphaGlu that are trapped in the ER, poorly transported or labile in the lysosomal environment. Chemical chaperone therapy could create new perspectives for therapeutic intervention in GSDII.
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twenty two novel mutations in the lysosomal α glucosidase gene gaa underscore the genotype phenotype correlation in glycogen storage disease type ii
Human Mutation, 2004Co-Authors: M M P Hermans, Marian A Kroos, Ans T Van Der Ploeg, Hitoshi Sakuraba, Dik Van Leenen, Clare E Beesley, Ron A Wevers, W J Kleijer, Helen Michelakakis, Edwin P KirkAbstract:Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to Acid Alpha-Glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the Acid Alpha-Glucosidase gene (GAA) encoding Acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on Acid Alpha-Glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.
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human Acid α glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type ii
Human Molecular Genetics, 1999Co-Authors: Agnes G A Bijvoet, Marian A Kroos, Hans Van Hirtum, Esther H M Van De Kamp, Onard Schoneveld, Pim Visser, Just P J Brakenhoff, Miranda Weggeman, Emile Van Corven, Ans T Van Der PloegAbstract: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.
