The apparent activity in vivo of the lysosomal pathway of glycogen catabolism in cultured human skin fibroblasts from patients with type III glycogen storage disease.

Brown, David H.; Waindle, Louise M.; Brown, Barbara I.

doi:10.1016/s0021-9258(17)34648-3

Cited by 34 publications

(4 citation statements)

References 28 publications

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“…It is well-known that α-amylase is found in the saliva, pancreatic juices, blood, and urine. Some amounts of polysaccharides, including starch, are known to be degraded intracellularly by various enzymes. − In addition, the existence of amylase-producing tumors has been reported, , which could be also a good target for α-amylase degradable starch-based delivery systems.…”

Section: Introductionmentioning

confidence: 99%

Design of Starch-graft-PEI Polymers: An Effective and Biodegradable Gene Delivery Platform

2014

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Starch and starch derivatives are widely utilized pharmaceutical excipients. The concept of this study was to make use of starch as a biodegradable backbone and to modify it with low-toxic, but poor transfecting low molecular weight polyethylenimine (PEI) in order to achieve better transfection efficacy while maintaining enzymatic degradability. A sufficiently controllable conjugation could be achieved via a water-soluble intermediate of oxidized starch and an optimized reaction protocol. Systematic variation of MW fraction of the starch backbone and the amount of cationic side chains (0.8 kDa bPEI) yielded a series of starch-graft-PEI copolymers. Following purification and chemical characterization, nanoscale complexes with plasmid DNA were generated and studied regarding cytotoxicity and transfection efficacy. The optimal starch-graft-PEI polymers consisted of >100 kDa MW starch and contained 30% (wt) of PEI, showing similar transfection levels as 25 kDa bPEI, and being less cytotoxic and enzymatically biodegradable.

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Section: Introductionmentioning

confidence: 99%

Design of Starch-graft-PEI Polymers: An Effective and Biodegradable Gene Delivery Platform

2014

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“…However, since glycogen is not homogeneous, such a determination may be difficult to achieve without a better understanding of the structure of glycogen. It should be kept in mind that such experiments would not account for ongoing replenishment of lysosomal glycogen by phagocytosis which is assumed to be the case for turnover in lysosomal function in tissues and has been demonstrated in fibroblast culture [29]. One would assume that the lysosomal population would reflect a steady state appearance of glycogen uptake and degradation but the real time case may be more complex than that.…”

Section: Discussionmentioning

confidence: 99%

The Release of a Soluble Glycosylated Protein from Glycogen by Recombinant Lysosomal α-Glucosidase (rhGAA) In Vitro and Its Presence in Serum In Vivo

Murray¹

2020

Biomolecules

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In studies on the degradation of glycogen by rhGAA, a glycosylated protein core material was found which consists of about 5–6% of the total starting glycogen. There was an additional 25% of the glycogen unaccounted for based on glucose released. After incubation of glycogen with rhGAA until no more glucose was released, no other carbohydrate was detected on HPAEC-PAD. Several oligosaccharides are then detectable if the medium is first boiled in 0.1 N HCl or incubated with trypsin. It is present in serum either in an HCl extract or in a trypsin digest. The characteristics of the in vivo serum material are identical to the material in the in vitro incubation medium. One oligosaccharide cannot be further degraded by rhGAA, from the incubation medium as well as from serum co-elute on HPAEC-PAD. Several masked oligosaccharides in serum contain m-inositol, e-inositol, and sorbitol as the major carbohydrates. The presence of this glycosylated protein in serum is a fraction of glycogen that is degraded outside the lysosome and the cell. The glycosylated protein in the serum is not present in the serum of Pompe mice not on ERT, but it is present in the serum of Pompe disease patients who are on ERT, so it is a biomarker of GAA degradation of lysosomal glycogen.

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“…Brown et. al., in their elegant study of glycogen degradation in debrancher deficient fibroblasts, investigated glycogen degradation by the lysosomal pathway [45]. They concluded that the lysosomal degradation of glycogen only proceeded at about 1% of the rate of glycogen degradation by the lysosomal α-glucosidase under optimal conditions [40].…”

Section: Deficiency In Pompe Diseasementioning

confidence: 99%

The Action of Recombinant Human Lysosomal α-Glucosidase (rhGAA) on Human Liver Glycogen: Pathway to Complete Degradation

Murray¹

2021

IJTM

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Glycogen is present in all tissues, but it is primarily stored in the liver and in muscle. As a branched chain carbohydrate, it is broken down by phosphorylase and debrancher enzymes, which are cytoplasmic. It is also degraded by a lysosomal α-glucosidase (GAA) also known as acid α-glucosidase and lysosomal acid α-glucosidase. The deficiency of GAA in patients is known as Pompe disease, and the phenotypes as infantile, juvenile and later onset forms. Pompe disease is treated by enzyme replacement therapy (ERT) with a recombinant form of rhGAA. Following ERT in Pompe mice and human patients there is residual carbohydrate material present in the cytoplasm of cells. The goal of this work is to improve ERT and attempt to identify and treat the residual cytoplasmic carbohydrate. Initial experiments were to determine if rhGAA can completely degrade glycogen. The enzyme cannot completely degrade glycogen. There is a residual glycosylated protein as well as a soluble glycosylated protein, which is a terminal degradation product of glycogen and as such serves as a biomarker for lysosomal glycogen degradation. The glycosylated protein has a very unusual carbohydrate composition for a glycosylated protein: m-inositol, s-inositol and sorbitol as the major carbohydrates, as well as mannitol, mannose, glucose and galactose. This work describes the residual material which likely contains the same protein as the soluble glycosylated protein. The biomarker is present in serum of control and Pompe patients on ERT, but it is not present in the serum of Pompe mice not on ERT. Pompe mice not on ERT have another glycosylated protein in their serum which may be a biomarker for Pompe disease. This protein has multiple glycosylation sites, each with different carbohydrate components. These glycosylated proteins as well as the complexity of glycogen structure are discussed, as well as future directions to try to improve the outcome of ERT for Pompe patients by being able to monitor the efficacy of ERT in the short term and possibly to adjust the timing and dose of enzyme infusions.

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The apparent activity in vivo of the lysosomal pathway of glycogen catabolism in cultured human skin fibroblasts from patients with type III glycogen storage disease.

Cited by 34 publications

References 28 publications

Design of Starch-graft-PEI Polymers: An Effective and Biodegradable Gene Delivery Platform

Design of Starch-graft-PEI Polymers: An Effective and Biodegradable Gene Delivery Platform

The Release of a Soluble Glycosylated Protein from Glycogen by Recombinant Lysosomal α-Glucosidase (rhGAA) In Vitro and Its Presence in Serum In Vivo

The Action of Recombinant Human Lysosomal α-Glucosidase (rhGAA) on Human Liver Glycogen: Pathway to Complete Degradation

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