title: Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent.
abstract: 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.
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida, United States of America; Department of Medicine, Center for Infection Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Sushrusha
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Doerfler
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Porvasnik
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Cloutier
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Richie
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Amicus Therapeutics Inc., Cranbury, New Jersey, United States of America.
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Valenzano
authors.affiliation: Department of Pediatrics, Cellular and Molecular Therapy, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.affiliation: Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000818:Animals; D003429:Cross Reactions / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D007110:Immunity, Active / Q000235:genetics*; D051379:Mice; D009154:Mutation; D019851:Thrombophilia / Q000235:genetics*; D000520:alpha-Glucosidases / Q000627:therapeutic use*
chemical_list: C509951:GAA protein, human; D000520:alpha-Glucosidases