Recombinant human acid α-glucosidase enzyme therapy for infantile glycogen storage disease type II: Results of a phase I/II clinical trial

Amalfitano, Andrea; Bengur, A. Resai; Morse, Richard P.; Majure, Joseph M.; Case, Laura E.; Veerling, Deborah L.; Mackey, Joanne; Kishnani, Priya S.; Smith, Wendy E.; McVie‐Wylie, Alison; Sullivan, Jennifer; Hoganson, George; Phillips, John A.; Schaefer, Gerald; Charrow, Joel; Ware, Russell E.; Bossen, Edward H.; Chen, Yuan Tsong

doi:10.1038/gim200127

Cited by 152 publications

(96 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Enzyme replacement therapy has been proven to be an effective means of treating lysosomal storage diseases (24,25). With respect to ASM, it has been shown that a recombinant form of the enzyme, expressed in CHO cells, has characteristics consistent with the non-recombinant forms including acid pH optimum, sensitivity to sulfhydryl reducing reagents, and inhibition by a zinc-specific chelator (8).…”

Section: Acid Sphingomyelinase (Asm)mentioning

confidence: 99%

Activation of Human Acid Sphingomyelinase through Modification or Deletion of C-terminal Cysteine

Qiu¹,

Edmunds²,

Baker-Malcolm³

et al. 2003

Journal of Biological Chemistry

131

119

View full text Add to dashboard Cite

One form of Niemann-Pick disease is caused by a deficiency in the enzymatic activity of acid sphingomyelinase. During efforts to develop an enzyme replacement therapy based on a recombinant form of human acid sphingomyelinase (rhASM), purified preparations of the recombinant enzyme were found to have substantially increased specific activity if cell harvest media were stored for several weeks at ؊20°C prior to purification. This increase in activity was found to correlate with the loss of the single free thiol on rhASM, suggesting the involvement of a cysteine residue. It was demonstrated that a variety of chemical modifications of the free cysteine on rhASM all result in substantial activation of the enzyme, and the modified cysteine responsible for this activation was shown to be the C-terminal residue (Cys 629 ). Activation was also achieved by copper-promoted dimerization of rhASM (via cysteine) and by Cterminal truncation using carboxypeptidase Y. The role of the C-terminal cysteine in activation was confirmed by creating mutant forms of rhASM in which this residue was either deleted or replaced by a serine, with both forms having substantially higher specific activity than wild-type rhASM. These results indicate that purified rhASM can be activated in vitro by loss of the free thiol on the C-terminal cysteine via chemical modification, dimerization, or deletion of this amino acid residue. This method of activation is similar to the cysteine switch mechanism described previously for matrix metalloproteinases and could represent a means of posttranslational regulation of ASM activity in vivo.

show abstract

Section: Acid Sphingomyelinase (Asm)mentioning

confidence: 99%

Activation of Human Acid Sphingomyelinase through Modification or Deletion of C-terminal Cysteine

Qiu¹,

Edmunds²,

Baker-Malcolm³

et al. 2003

Journal of Biological Chemistry

131

119

View full text Add to dashboard Cite

show abstract

“…At present, there is not an effective treatment for AMD patients; however, enzyme-replacement therapy (ERT) based therapeutics are being clinically tested [2,3]. This is because lysosomal enzymes have targeting characteristics that may be capitalized upon for the treatment of diseases such as AMD.…”

Section: Introductionmentioning

confidence: 99%

Multiple muscles in the AMD quail can be “cross‐corrected” of pathologic glycogen accumulation after intravenous injection of an [E1‐, polymerase‐] adenovirus vector encoding human acid‐α‐glucosidase

McVie‐Wylie

Ding

Lawson

et al. 2002

The Journal of Gene Medicine

View full text Add to dashboard Cite

Adenovirus-mediated transduction of the hGAA gene, followed by hepatic secretion, uptake, and cross-correction of the pathologic glycogen accumulation noted in multiple muscles of both the AMD mouse and AMD quail, adds support to the notion that gene transfer strategies (Ad-mediated or other agents) targeting liver tissues with the hGAA gene are likely to be highly efficacious in humans affected by AMD.

show abstract

“…Enzyme replacement therapy (ERT) using recombinant enzyme, which is designed to be incorporated by the mannose 6-phosphate (M6P) receptor and targeted to lysosomes, is available in some lysosomal storage disorders such as Fabry disease, Gaucher disease, Pompe disease, and various mucopolysaccharidoses, whereas many other therapies that enhance enzyme activities or reduce substrates are undergoing clinical trials for many different lysosomal storage disorders (7)(8)(9)(10)(11)(12)(13). In the case of ML-II, however, there is no ERT to date as lysosomes lack dozens of enzymes targeted by the M6P receptor-dependent pathway.…”

mentioning

confidence: 99%

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Otomo

Higaki

Nanba

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mucolipidosis II (ML-II) is a fatal inherited metabolic disease caused by deficiency of GlcNAc-phosphotransferase, which plays a role in generating the mannose 6-phosphate recognition marker on lysosomal enzymes. In ML-II, many lysosomal acid hydrolases are mistargeted out of cells, and lysosomes become filled with undigested substrates, which explains inclusion cell disease as an alternative name for this disease. In this study, we revealed various cellular phenotypes in ML-II skin fibroblasts. We quantitated phospholipid and cholesterol within cells and showed ϳ2-fold accumulation in ML-II as compared with normal cells. Lysosomal pH of ML-II cells was higher than that of normal cells (5.29 ؎ 0.08 versus 4.79 ؎ 0.10, p < 0.001). The proliferated lysosomes in ML-II cells were accumulated ϳ3-fold in amount as compared with normal cells. Intracellular logistics including endocytosis and mannose 6-phosphate receptor recycling were impaired in ML-II cells. To confirm whether these ML-II cellular phenotypes derive from deficient lysosomal acid hydrolases within lysosomes, we performed supplementation of lysosomal enzymes using a partially purified total enzyme mixture, which was derived from the conditioned culture medium of normal skin fibroblasts after NH 4 Cl treatment. This supplementation corrected all of the previously described ML-II phenotypes. In addition, the autophagic and mitochondrial impairment that we have previously reported improved, and inclusion bodies disappeared on electron micrography following total lysosomal enzyme supplementation. Our results indicate that various cellular phenotypes in ML-II are caused by the deficiency of many lysosomal enzymes and massive accumulation of undigested substrates.

show abstract

Recombinant human acid α-glucosidase enzyme therapy for infantile glycogen storage disease type II: Results of a phase I/II clinical trial

Abstract: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.

Cited by 152 publications

References 16 publications

Activation of Human Acid Sphingomyelinase through Modification or Deletion of C-terminal Cysteine

Activation of Human Acid Sphingomyelinase through Modification or Deletion of C-terminal Cysteine

Multiple muscles in the AMD quail can be “cross‐corrected” of pathologic glycogen accumulation after intravenous injection of an [E1‐, polymerase‐] adenovirus vector encoding human acid‐α‐glucosidase

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Contact Info

Product

Resources

About