Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I.

Abstract:

:Immune responses can interfere with the effective use of therapeutic proteins to treat genetic deficiencies and have been challenging to manage. To address this problem, we adapted and studied methods of immune tolerance used in canine organ transplantation research to soluble protein therapeutics. A tolerization regimen was developed that prevents a strong antibody response to the enzyme alpha-l-iduronidase during enzyme replacement therapy of a canine model of the lysosomal storage disorder mucopolysaccharidosis I. The tolerizing regimen consists of a limited 60-day course of cyclosporin A and azathioprine combined with weekly i.v. infusions of low-dose recombinant human alpha-l-iduronidase. The canines tolerized with this regimen maintain a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptor-mediated uptake because alpha-l-iduronidase and alpha-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated alpha-l-iduronidase did not. This tolerization method should be applicable to the treatment of other lysosomal storage disorders and provides a strategy to consider for other nontoleragenic therapeutic proteins and autoimmune diseases.

authors

Kakkis E,Lester T,Yang R,Tanaka C,Anand V,Lemontt J,Peinovich M,Passage M

doi

10.1073/pnas.0305480101

keywords:

subject

Has Abstract

pub_date

2004-01-20 00:00:00

pages

829-34

issue

3

eissn

0027-8424

issn

1091-6490

pii

0305480101

journal_volume

101

pub_type

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