Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice

Nina Raben, Kanneboyina Nagaraju, Alicia Lee, Nina Lu, Yesenia Rivera, Tejas Jatkar, John J. Hopwood, Paul H. Plotz

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


When knockout mice are used to test the efficacy of recombinant human proteins, the animals often develop antibodies to the enzyme, precluding long-term pre-clinical studies. This has been a problem with a number of models, for example, the evaluation of gene or enzyme replacement therapies in a knockout model of glycogen storage disease type II (GSDII; Pompe syndrome). In this disease, the lack of acid alpha-glucosidase (GAA) results in lysosomal accumulation of glycogen, particularly in skeletal and cardiac muscle. Here, we report that in a GAA-deficient mouse model of GSDII, low levels of transgene-encoded human GAA expressed in skeletal muscle or liver dramatically blunt or abolish the immune response to human recombinant protein. Of two low expression transgenic lines, only the liver-expressing line exhibited a profound GAA deficiency in skeletal muscle and heart indistinguishable from that in the original knockouts. The study suggests that the induction of tolerance in animal models of protein deficiencies could be achieved by restricting the expression of a gene of interest to a particular, carefully chosen tissue.

Original languageEnglish (US)
Pages (from-to)171-178
Number of pages8
JournalTransgenic Research
Issue number2
StatePublished - Apr 2003
Externally publishedYes


  • Antibodies
  • Lysosomal disorder
  • Tetracycline inducible system
  • Tolerance
  • Transgenic/knockouts

ASJC Scopus subject areas

  • Genetics
  • Plant Science
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Biotechnology
  • Food Science


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