Chaperone Therapy for Sanfilippo C
Ste-Justine Hospital
Dr.Alexey Pshezhetsky alexei.pchejetski@umontreal.ca

The concept of the chaperone therapy is a novel idea in which a lead molecule is nominated from a library of candidates. This molecule is small enough to breach the Blood-Brain Barrier (BBB). Once the molecule enters the body it is attracted to the enzyme and theoretically will enter the enzyme and “prop up” the folded part of its mutation. This will allow the enzyme to pass through the cell and enter the body, where it can perform its job of breaking down the substrate, also called a sugar molecule. In our case that substrate is known as Heparan Sulfate. The molecule used for the chaperone therapy doesn’t perform like an average drug. It’s the shape of the molecule that matters here. We need an exact fit to help our kids, who have specific folds in their enzyme Partial restoration of the deficient activity of N-acetyltransferase, even if modest, could help alleviate the disease symptoms or drastically slow the disease progression. Experiments using patients cells demonstrated that glucosamine could partially restore the protein folding defect and increase its activity.

These results, published in the recent issue of PLoS ONE (Matthew Feldhammer, Stéphanie Durand and Alexey V. Pshezhetsky Protein Misfolding as an Underlying Molecular Defect in Mucopolysaccharidosis III Type C PLoS ONE, October 13th, 2009; http://dx.plos.org), may provide future therapeutic solutions for this devastating untreatable disease.

Recently, Pshezhetsky was awarded a grant of $650,000 from the Canadian Institute of Health.