Limits...
Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent.

Nayak S, Doerfler PA, Porvasnik SL, Cloutier DD, Khanna R, Valenzano KJ, Herzog RW, Byrne BJ - PLoS ONE (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH

Related in: MedlinePlus

A) Experimental timeline B) Core temperature measurements prior to and post the 8th rhGAA IV injection in wt 129 SVE and wt BALB/c mice (n = 5) C) Anti-rhGAA IgG1 antibody in 129SVE wt mice D) Anti-rhGAA IgG1 antibody in BALB/c mice E) Anti-rhGAA IgG2a antibody in wt 129SVE mice F) Anti-rhGAA IgG2a antibody in wt BALB/c mice.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4045583&req=5

pone-0098336-g001: A) Experimental timeline B) Core temperature measurements prior to and post the 8th rhGAA IV injection in wt 129 SVE and wt BALB/c mice (n = 5) C) Anti-rhGAA IgG1 antibody in 129SVE wt mice D) Anti-rhGAA IgG1 antibody in BALB/c mice E) Anti-rhGAA IgG2a antibody in wt 129SVE mice F) Anti-rhGAA IgG2a antibody in wt BALB/c mice.

Mentions: Wt BALB/c, wt 129SVE and P545L C57BL/6x129SVE mice were injected intravenously (IV) via tail-vein with 20 mg/kg rhGAA (Myozyme, Genzyme, MA) once every two weeks for eight weeks and re-challenged again ∼eight weeks later, once every two weeks for an additional eight weeks (Figure 1 A) in an attempt to elicit a more severe immune response. GAA-/- 129SVE mice were injected once every two weeks with 1 mg/kg, 5 mg/kg or 20 mg/kg for up to 10 weeks. All rhGAA doses were calculated on mouse weight of 25 g. Blood samples were obtained by tail-vein or retro-orbital into an anti-coagulant coated tube (heparin or 3.8% sodium citrate) for enzyme linked immunosorbent assay (ELISA), complete blood count (CBC), iSTAT and clotting assays.


Immune responses and hypercoagulation in ERT for Pompe disease are mutation and rhGAA dose dependent.

Nayak S, Doerfler PA, Porvasnik SL, Cloutier DD, Khanna R, Valenzano KJ, Herzog RW, Byrne BJ - PLoS ONE (2014)

A) Experimental timeline B) Core temperature measurements prior to and post the 8th rhGAA IV injection in wt 129 SVE and wt BALB/c mice (n = 5) C) Anti-rhGAA IgG1 antibody in 129SVE wt mice D) Anti-rhGAA IgG1 antibody in BALB/c mice E) Anti-rhGAA IgG2a antibody in wt 129SVE mice F) Anti-rhGAA IgG2a antibody in wt BALB/c mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4045583&req=5

pone-0098336-g001: A) Experimental timeline B) Core temperature measurements prior to and post the 8th rhGAA IV injection in wt 129 SVE and wt BALB/c mice (n = 5) C) Anti-rhGAA IgG1 antibody in 129SVE wt mice D) Anti-rhGAA IgG1 antibody in BALB/c mice E) Anti-rhGAA IgG2a antibody in wt 129SVE mice F) Anti-rhGAA IgG2a antibody in wt BALB/c mice.
Mentions: Wt BALB/c, wt 129SVE and P545L C57BL/6x129SVE mice were injected intravenously (IV) via tail-vein with 20 mg/kg rhGAA (Myozyme, Genzyme, MA) once every two weeks for eight weeks and re-challenged again ∼eight weeks later, once every two weeks for an additional eight weeks (Figure 1 A) in an attempt to elicit a more severe immune response. GAA-/- 129SVE mice were injected once every two weeks with 1 mg/kg, 5 mg/kg or 20 mg/kg for up to 10 weeks. All rhGAA doses were calculated on mouse weight of 25 g. Blood samples were obtained by tail-vein or retro-orbital into an anti-coagulant coated tube (heparin or 3.8% sodium citrate) for enzyme linked immunosorbent assay (ELISA), complete blood count (CBC), iSTAT and clotting assays.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus