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Safety evaluation of a second generation enzyme replacement therapy
Author(s) -
D'Angona Alida Louise,
Finn Patrick,
Murray James,
McVieWylie Alison,
Andrews Laura
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1179.1
Subject(s) - enzyme replacement therapy , lysosomal storage disease , sialic acid , glycogen , mannose 6 phosphate , lysosome , pharmacology , enzyme , chemistry , biochemistry , biology , receptor , medicine , disease , growth factor
Pompe disease (glycogen storage disease type II) is a lysosomal storage disease in which a deficiency of the enzyme acid‐alpha glucosidase (GAA) results in accumulation of glycogen primarily in the cardiac and skeletal muscles. Enzyme replacement therapy (ERT) utilizing recombinant human GAA (rhGAA, Myozyme/Lumizyme) currently represents the most effective therapeutic approach. While treatment with rhGAA has proven effective, it has been demonstrated that increasing mannose‐6‐phosphate (M6P) levels on rhGAA increases targeting to skeletal muscles through the M6P receptor resulting in improved glycogen clearance. The level of M6P on rhGAA has been increased by conjugating synthetic hexasaccaride glycans containing two terminal M6Ps via the sialic acid moieties on rhGAA (neoGAA). From a preclinical development perspective, neoGAA is an interesting molecule because it has components of both a small molecule (synthetic linker) and a biologic. A preclinical program was designed to include acute (pilot) and chronic toxicology studies, safety pharmacology and genetic toxicology studies. The results of these studies demonstrated no genotoxicity or toxicity associated with administration of neoGAA to both rodents and non‐human primates.