What is the concept behind enzyme replacement therapy?

Enzyme replacement therapy involves replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous (IV) infusion containing the enzyme. Other delivery techniques for eg. intrathecal administration of enzymes in Hurlers syndrome is under investigation.

The concept of ERT orginated decades ago. In 1968 Fratantoni et al reported that the biochemical defect of cultured skin fibroblasts from Hurler or Hunter patients may be corrected if cells of these two genotypes are mixed with each other or with normal cells, the effect being mediated by substances released into the medium.

enzymes and proteins produced in the cell are posttranslationally modified with certain markers, such as a mannose-6-phosphate moiety. These proteins are directed to the lysosome in which specific membrane receptors (in this instance, a mannose-6-phosphate membrane receptor) help endocytose the protein for use in the lysosome.The endosome combines with a dysfunctional lysosome, and the defective enzymes within the lysosome are replaced by functional exogenous enzymes.The accumulated storage material can then be metabolized, improving the overall function and structure of the lysosome.

In 1991 the FDA gave approval for Enzyme replacement therapy. ERT is currently available for 6 of the Lysosomal storage disorders¹.

Recombinant Enzyme	Disorder	Comment
Imiglucerase	Nonneuronopathic (type 1) Gaucher disease	reported to reduce hepatosplenomegaly, improve anemia and thrombocytopenia, and reduce episodes of pain crises in these patients.Because the recombinant enzyme does not cross the blood-brain barrier, it is not effective in type 2 Gaucher disease patients with severe CNS abnormalities
Alpha-galactosidase (2003)	Fabry disease	Improvement in pain and gastrointestinal symptoms has been reported,but long-term studies are required for evaluating its efficacy with respect to life-threatening complication
Laronidase (2003)	MPS I	reported improvements in hepatosplenomegaly and respiratory disease and showing a decrease in urinary glycosaminoglycan excretion. Hematopoietic Stem Cell Transplantation (HCT) is currently the mainstay of therapy for MPS I
Arylsulfatase B (2005)	MPS VI (Maroteaux-Lamy syndrome)	associated with improvements in hepatosplenomegaly, joint movement, cardiopulmonary function, and pain as well as reduced excretion of urinary glycosaminoglycans
Alglucosidase alpha	Infantile Pompe disease	A portion of infants who are diagnosed and treated with ERT before 6 months of age had improved survival and quality of life compared with the observed natural history of the disease, yet, for unknown reasons, a subset of the treated cohort did not show effects from ERT
Idursulfase	MPS II (Hunter syndrome)	Clinical trials showed improvement in cardiopulmonary disease and hepatosplenomegaly and decreased excretion of urinary glycosaminoglycans

Drawbacks:

1. ERT has little effect on the brain, skeletal tissue, and valvular heart disease in LSDs.
2. ERT treats only the symptoms and not the underlying disease
3. Lifelong frequent infusions (weekly to monthly depending on the protocol)
4. The estimated cost of ERT is between $90,000 to $565,000 (US), depending on the disease (therapy) and patient size.
5. Infusion reactions including fatal anaphylaxis have been reported

References:

1.Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol. 2008 Sep ;15(3):119-26.

Contributors to this page

Biju Hameed