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 are exploring modifications to the enzyme and new delivery systems. We have consisdered chemically modifying the enzyme with Polyethylene Glycol (PEG) to increase plasma survival. Modifications to glucocerebrosidase 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 subcutaneous or oral delivery. Recombinant active protein/enzyme production in the milk of transgenic animals have also been investigated with different DNA constructs containing the human glucocerebrosidase gene and a variety of mammary gland promoter sequences. The concept of chemical chaperone therapy is being considered by exploring whether small molecules may enhance the delivery of mutant glucocerebrosidase to the lysosome.The role of alternate substrates in Gaucher disease are being studied with an emphasis on glucosylsphingosine.Lastly, environmental factors contributing to symptomology in this disorder are being explored with the strategy that therapy might best be specifically directed to patients during times of anticipated stress.