Transgenic mouse model for developing enzyme replacement therapy for iduronate-2-sulfatase deficiency syndrome

A transgenic mouse tolerant to human iduronate-2-sulfatase without generating anti-IDS IgG antibody prepared by the steps comprising:

• i) preparing an iduronate-2-sulfatase knock-out mouse comprising disruption in exon 2 and exon 3 in the iduronate-2-sulfatase gene, wherein said disruption has been introduced into its genome by homologous recombination with DNA targeting construct in an embryonic stem cell such that the targeting construct is stably integrated in the genome of said mouse, wherein the disruption of the iduronate-2-sulfatase gene results in an inability of said mouse to produce detectable levels of iduronate-2-sulfatase;
• ii) preparing an iduronate-2-sulfatase mutation mouse comprising site direct mutagenesis of iduronate-2-sulfatase gene, wherein cysteine, the 84.sup.th amino acid of human iduronate-2-sulfatase of SEQ ID No:1 is replaced by threonine (C84T) or arginine, the 88.sup.th amino acid of human iduronate-2-sulfatase of SEQ ID No:1 is replaced by proline (R88P), wherein said mutation has been introduced into its genome with DNA targeting construct in an embryonic stem cell such that the targeting construct is stably integrated in the genome of said mouse, wherein the mutation of the iduronate-2-sulfatase gene results in capability of said mouse to produce inactive type of iduronate-2-sulfatase;
• and
• iii) cross-breeding the knock-out mouse prepared in step (i)and the mutation mouse prepared in step (ii) for obtaining the transgenic mouse tolerant to iduronate-2-sulfatase.