We aim to develop novel drugs for MPS II with the potential to reach and effectively treat the brain. Our approach is via so-called Pharmacological Chaperone Therapy (or PCT), also known as enzyme enhancement therapy. This approach has shown promise in other lysosomal storage disorders but has yet to be developed for the mucopolysaccharidoses such as MPS II. PCT uses a small molecule (a “chaperone”) that is specially designed to attach itself to the defective enzyme (iduronate-2-sulfatase in this case) to stabilize it and, chaperone‟ it safely to the lysosome so it can do its intended job, which is to break down and reduce storage of mucopolysaccharides. We aim to synthesize small molecules that bind tightly to iduronate-2-sulfatase suitable for testing as MPS II chaperones. We have prepared advanced intermediates suitable for this purpose and will convert them into a range of target compounds for testing. Once in hand these compounds will be evaluated in cultured skin cells derived from MPS II patients for their ability to bind the mutant enzyme and reduce the amount of stored mucopolysaccharides. The most promising compounds will then be selected for further testing in a mouse model of MPS II.
– Vito Ferro, PhD
University of Queensland Brisbane, Queensland Australia