Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent.
Enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) is the only FDA approved therapy for Pompe disease. Without ERT, severely affected individuals (early onset) succumb to the disease within 2 years of life. A spectrum of disease severity and progression exists dependi...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4045583?pdf=render |
| _version_ | 1828964349023092736 |
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| author | Sushrusha Nayak Phillip A Doerfler Stacy L Porvasnik Denise D Cloutier Richie Khanna Ken J Valenzano Roland W Herzog Barry J Byrne |
| author_facet | Sushrusha Nayak Phillip A Doerfler Stacy L Porvasnik Denise D Cloutier Richie Khanna Ken J Valenzano Roland W Herzog Barry J Byrne |
| author_sort | Sushrusha Nayak |
| collection | DOAJ |
| description | Enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) is the only FDA approved therapy for Pompe disease. Without ERT, severely affected individuals (early onset) succumb to the disease within 2 years of life. A spectrum of disease severity and progression exists depending upon the type of mutation in the GAA gene (GAA), which in turn determines the amount of defective protein produced and its enzymatic activity. A large percent of the early onset patients are also cross reactive immunological material negative (CRIM-) and develop high titer immune responses to ERT with rhGAA. New insights from our studies in pre-clinical murine models reveal that the type of Gaa mutation has a profound effect on the immune responses mounted against ERT and the associated toxicities, including activation of clotting factors and disseminated intravascular coagulation (DIC). Additionally, the mouse strain affects outcomes, suggesting the influence of additional genetic components or modifiers. High doses of rhGAA (20 mg/kg) are currently required to achieve therapeutic benefit. Our studies indicate that lower enzyme doses reduce the antibody responses to rhGAA, reduce the incidence of immune toxicity and avoid ERT-associated anaphylaxis. Therefore, development of rhGAA with increased efficacy is warranted to limit immunotoxicities. |
| first_indexed | 2024-12-14T10:48:00Z |
| format | Article |
| id | doaj.art-c18505096a00432ab147b4446c7d4dfe |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T10:48:00Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c18505096a00432ab147b4446c7d4dfe2022-12-21T23:05:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0196e9833610.1371/journal.pone.0098336Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent.Sushrusha NayakPhillip A DoerflerStacy L PorvasnikDenise D CloutierRichie KhannaKen J ValenzanoRoland W HerzogBarry J ByrneEnzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA) is the only FDA approved therapy for Pompe disease. Without ERT, severely affected individuals (early onset) succumb to the disease within 2 years of life. A spectrum of disease severity and progression exists depending upon the type of mutation in the GAA gene (GAA), which in turn determines the amount of defective protein produced and its enzymatic activity. A large percent of the early onset patients are also cross reactive immunological material negative (CRIM-) and develop high titer immune responses to ERT with rhGAA. New insights from our studies in pre-clinical murine models reveal that the type of Gaa mutation has a profound effect on the immune responses mounted against ERT and the associated toxicities, including activation of clotting factors and disseminated intravascular coagulation (DIC). Additionally, the mouse strain affects outcomes, suggesting the influence of additional genetic components or modifiers. High doses of rhGAA (20 mg/kg) are currently required to achieve therapeutic benefit. Our studies indicate that lower enzyme doses reduce the antibody responses to rhGAA, reduce the incidence of immune toxicity and avoid ERT-associated anaphylaxis. Therefore, development of rhGAA with increased efficacy is warranted to limit immunotoxicities.http://europepmc.org/articles/PMC4045583?pdf=render |
| spellingShingle | Sushrusha Nayak Phillip A Doerfler Stacy L Porvasnik Denise D Cloutier Richie Khanna Ken J Valenzano Roland W Herzog Barry J Byrne Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. PLoS ONE |
| title | Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. |
| title_full | Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. |
| title_fullStr | Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. |
| title_full_unstemmed | Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. |
| title_short | Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent. |
| title_sort | immune responses and hypercoagulation in ert for pompe disease are mutation and rhgaa dose dependent |
| url | http://europepmc.org/articles/PMC4045583?pdf=render |
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