High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa

Vries, Juna M. de; Beek, Nadine A.M.E. van der; Kroos, Marian A.; Özkan, Lale; Doorn, Pieter A. van; Richards, Susan; Sung, Crystal; Brugma, Jan-Dietert C.; Zandbergen, Adrienne A.M.; Ploeg, Ans T. van der; Reuser, Arnold

doi:10.1016/j.ymgme.2010.08.009

Cited by 92 publications

(119 citation statements)

References 35 publications

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“…53,62 Data from our own cohort, as well as the data from Patel et al, attest that peaks of anti-rhGAA IgG antibody titers can occur even after several years of ERT. 63 However, a clear correlation between anti-rhGAA IgG titer and clinical outcome under ERT cannot be found.…”

supporting

confidence: 59%

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

Schneider¹,

Zierz²

2016

RRED

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Pompe disease, also referred to as glycogenosis type II, is a rare, autosomal recessive disorder that results from the deficiency of the glycogen-degrading enzyme acid α-glucosidase. The classical form presents shortly after birth with muscle hypotonia, cardiac, and respiratory failure resulting in a fatal outcome. The late onset of Pompe disease has a very variable onset and disease presentation that often causes a delayed diagnosis. Until now enzyme replacement therapy with alglucosidase alfa is the only causative therapy option for Pompe patients that can slow down disease progression. However, uncertainty remains about the efficacy regarding survival and quality of life in Pompe patients under this very cost-intensive treatment. This paper provides a systematic review of the literature stressing different aspects of enzyme replacement therapy in infantile and late onset Pompe patients.

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supporting

confidence: 59%

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

Schneider¹,

Zierz²

2016

RRED

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“…Understanding the mechanism of how glycogen is transported into lysosomes is a critical step for the exploration of new therapeutic targets for Pompe disease considering the significant limitations of enzyme replacement therapy (7)(8)(9). It has been demonstrated that autophagy plays a partial role in the transport of glycogen to lysosomes in skeletal muscle of GAA-KO mice (12), which suggests that other route(s) also exist for this process.…”

Section: Discussionmentioning

confidence: 99%

“…Enzyme replacement therapy with recombinant human GAA is the only available therapy for this disorder to have remarkable success, but it also has significant limitations such as high titer antibody formation and difficulties in delivering the therapeutic protein to skeletal muscle tissues (7)(8)(9)(10)(11). A conceivable alternative way to treat Pompe disease would be to block the transport of cytoplasmic glycogen to the lysosomes.…”

mentioning

confidence: 99%

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Sun¹,

Yi²,

Yang

et al. 2016

Journal of Biological Chemistry

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A small portion of cellular glycogen is transported to and degraded in lysosomes by acid ␣-glucosidase (GAA) in mammals, but it is unclear why and how glycogen is transported to the lysosomes. Stbd1 has recently been proposed to participate in glycogen trafficking to lysosomes. However, our previous study demonstrated that knockdown of Stbd1 in GAA knockout mice did not alter lysosomal glycogen storage in skeletal muscles. To further determine whether Stbd1 participates in glycogen transport to lysosomes, we generated GAA/Stbd1 double knock-out mice. In fasted double knock-out mice, glycogen accumulation in skeletal and cardiac muscles was not affected, but glycogen content in liver was reduced by nearly 73% at 3 months of age and by 60% at 13 months as compared with GAA knock-out mice, indicating that the transport of glycogen to lysosomes was suppressed in liver by the loss of Stbd1. Exogenous expression of human Stbd1 in double knock-out mice restored the liver lysosomal glycogen content to the level of GAA knock-out mice, as did a mutant lacking the Atg8 family interacting motif (AIM) and another mutant that contains only the N-terminal 24 hydrophobic segment and the C-terminal starch binding domain (CBM20) interlinked by an HA tag. Our results demonstrate that Stbd1 plays a dominant role in glycogen transport to lysosomes in liver and that the N-terminal transmembrane region and the C-terminal CBM20 domain are critical for this function.Liver and muscle are the two primary sites for glycogen metabolism in mammals. Glycogen is synthesized and mostly degraded in the cytoplasm, but a small percentage of glycogen is transported into the lysosomes and hydrolyzed by the enzyme acid ␣-glucosidase (GAA) 3 (1-3). Deficiency of GAA causes Pompe disease (glycogen storage disease type II), resulting in a progressive lysosomal glycogen accumulation and dysfunction in cardiac and skeletal muscle and other tissues (4 -6). Enzyme replacement therapy with recombinant human GAA is the only available therapy for this disorder to have remarkable success, but it also has significant limitations such as high titer antibody formation and difficulties in delivering the therapeutic protein to skeletal muscle tissues (7-11). A conceivable alternative way to treat Pompe disease would be to block the transport of cytoplasmic glycogen to the lysosomes. Thus, understanding how glycogen enters the lysosome is a critical step in finding new therapeutic targets for Pompe disease. It has been demonstrated that conventional autophagy (macroautophagy) plays an important role in the transport of glycogen to lysosomes in skeletal muscle (12). Specifically, knock-out of an autophagy key gene Atg7 resulted in a decrease of glycogen content by 50 -60% in skeletal muscles of GAA knock-out mice (12). This suggests that other routes exist for glycogen transport to lysosomes. In recent studies, starch binding domain-containing protein 1 (Stbd1) has gained attention for its potential involvement in glycogen transport. The Stbd1 protein contains a putat...

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“…In recent years, the functionally active nature of alloantibodies and the catastrophic effects of the alloimmune response in some LSD [11][12] were recognized and led to efforts to develop an effective and quick immune tolerance induction regimen. These strategies had variable outcomes and serious side effects were reported in some cases.…”

Section: Discussionmentioning

confidence: 99%

“…7,[10][11][12] Several clinical protocols for the induction of immune tolerance to exogenous enzyme have been reported for these diseases and others, including hemophiliac disorders 13 in which there is a similar host immune response against a foreign protein. Allogeneic hematopoietic stem cell transplantation (HSCT) can replace the recipient's immune system with that of the donor, thereby tolerizing the individual to the replaced enzyme (pharmacological or cellular).…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Saif¹,

Bigger²,

Brookes³

et al. 2012

Haematologica

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BackgroundMucopolysaccharidosis type I is caused by deficiency of a-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of allo-immune responses in these patients remain unknown. Design and MethodsWe developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. ResultsHigh titer immune responses were seen in 87.5% (7/8) patients following exposure to a-Liduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. ConclusionsWe found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy. © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n

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High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa

Cited by 92 publications

References 35 publications

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

Starch Binding Domain-containing Protein 1 Plays a Dominant Role in Glycogen Transport to Lysosomes in Liver

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

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