Treatment Strategies For Gaucher Disease

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

Attractive and logical treatment strategies for human genetic disorders resulting from a single gene defect include enzyme replacement and enhancement. 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. 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 explained by exploring the trafficking of glucocerebrosidase and investigating whether small molecules may enhance the delivery of mutant glucocerebrosidase to the lysosome. In collaboration with Dr. Chris Austin (NHGRI), we are screening large libraries of compounds in an attempt to identify candidate chaperones. The role of alternate substrates in Gaucher disease is also 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.