Enzyme Replacement Strategies for Inborn Errors of Metabolism

Sidransky, E.

Abstract

A treatment strategy for human genetic disorders resulting from a single gene defect is direct protein/enzyme replacement. We are recombinantly producing human proteins/enzymes, some of which can be further modified to enhance their clinical effectiveness. Recombinant human proteins that are under study include lysosomal enzymes (glucocerebrosidase and `- galactosidase), neurotransmitter synthesizing enzymes (tyrosine hydroxylase and tryptophan hydroxylase) and other proteins (saprosin proteins). Active recombinant human glucocerebrosidase is being produced in large amounts using a baculovirus expression system. As a potential alternative therapy to Alglucerase which is clinically useful in Gaucher patients but is quite costly, human glucocerebrosidase produced using the baculovirus expression system is chemically modified with Polyethylene Glycol (PEG) to increase plasma survival. This chemical modification may potentially offer significant benefit to patients by decreasing drug cost, antigenicity and dosage, and providing a more convenient route of administration, such as intramuscular or subcutaneous delivery. A Phase I drug study testing the safety, pharmacodynamics, pharmacokinetics and efficacy of PEG-glucocerebrosidase is now underway. Other human proteins/enzymes, including saprosin proteins are also being recombinantly produced. Recombinant active enzymes are also being produced in the milk of transgenic animals. Different DNA constructs containing the human glucocerebrosidase gene and a variety of mammary gland promoters with and without matrix attachment regions have been used to create transgenic mice which express human glucocerebrosidase in their milk. These constructs are now being optimized and tested in pigs to enable the production of large quantities of therapeutically useful proteins.