Enzyme Replacement Strategies For Inborn Errors Of Metab

Sidransky, Ellen

Abstract

An attractive and logical treatment strategy for human genetic disorders resulting from a single gene defect is direct protein/enzyme replacement. We study recombinantly produced human proteins/enzymes, some of which can be further modified to enhance their clinical effectiveness. Recombinant human proteins that are under evaluation include lysosomal enzymes, especially glucocerebrosidase. Enzyme replacement therapy for Gaucher disease with Imiglucerase has been shown to be clinically effective, but its extremely high cost is of considerable concern both to the public and to health care providers. As a potential alternative therapy to Imiglucerase, we have explored chemically modifying the enzyme 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 also by providing a more convenient route of administration, such as intramuscular or subcutaneous delivery. Recombinant active protein/enzyme production in the milk of transgenic animals have also been investigated. Different DNA constructs containing the human glucocerebrosidase gene and a variety of mammary gland promoter sequences have been used to create transgenic mice which express high levels of human glucocerebrosidase in their milk. The concept of synergistic heterozygousity is being considered by quantifying levels of the enzyme glucosylceramide synthetase in specific patients. Lastly, environmental factors contributing to symptomology in this order are being explained with the strategy that therapy might best be specifically directed to patients during times of anticipated stress.