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Type: Journal article
Title: Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice
Author: Raben, N.
Nagaraju, K.
Lee, A.
Lu, N.
Rivera, Y.
Jatkar, T.
Hopwood, J.
Plotz, P.
Citation: Transgenic Research, 2003; 12(2):171-178
Publisher: Kluwer Academic Publ
Issue Date: 2003
ISSN: 0962-8819
Statement of
Nina Raben, Kanneboyina Nagaraju, Alicia Lee, Nina Lu, Yesenia Rivera, Tejas Jatkar, John J. Hopwood, Paul H. Plotz
Abstract: 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.
Keywords: Liver; CHO Cells; Animals; Mice, Transgenic; Mice, Knockout; Humans; Mice; Glycogen Storage Disease Type II; Disease Models, Animal; alpha-Glucosidases; Recombinant Proteins; Autoantibodies; Phenotype; Cricetinae
RMID: 0020031258
DOI: 10.1023/A:1022998010833
Appears in Collections:Paediatrics publications

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