The main focus of my work is the investigation of the complex series of events at the cellular and tissue level that are at play in the evolution and of genetic disease. It is hoped that an understanding of disease at this level will result in the development of specific forms of therapy for rare genetic disease. My group has chosen to focus on a series of devastating progressive disorders termed lysosomal storage diseases.

Clinical trial of recombinant iduronidase in the treatment of MPSI
Clinical trial of recombinant iduronidase in the treatment of MPSI

This is a complex multicenter multinational clinical trial of the use of iduronidase for the treatment of the genetic disease MPS I.

Proteomic approach to the identification of biomarkers of MPS disease
This project involves the identification, through serum proteomic studies, markers of disease severity and responsiveness. Markers will initially be identified in a murine model and subsequently validated in human samples.

Clinical trial of BH4 for the treatment of classical PKU
It has now been suggested that small molecules can act as chemical chaperones for misfolded proteins that are caused by point mutations of genes. PKU is an inborn error of metabolism that is currently treated by very restrictive diet. In vitro studies have shown that BH4 can stabilize mutant PAH enzyme and lead to greater tolerance of PHE in the diet.

Rempel, B.P., Clarke, L.A. , Withers, S.G. A homology model for human alpha-L-iduronidase: insights into human disease. Molecular Genetics and Metabolism, 2005, available online February 2005.

James E. Wraith, Lorne A. Clarke, Michael Beck, Edwin H. Kolodny, Gregory M. Pastores, Joseph Muenzer, David Rapoport, Kenneth Berger, Stuart Swiedler, Emil Kakkis, Tanja Braakman, Elenie Chadbourne, Karen Walton-Bowen, Gerald Cox. Enzyme replacement therapy for Mucopolysaccharidosis I: A randomized, double-blind, placebo-controlled, multinational study of recombinant human a-L-iduronidase (Laronidase). Journal of Pediatrics, 144(5):581-8, May 2004.

Vallance, H., Chaba, T., Clarke, L.A. , Taylor , G. Pseudo-lysosomal storage disease caused by EMLA cream.Journal of Inherited Metabolic Dis., 27(4):507-11, 2004.

Nieman, C.E., Wong, A.W., He, S., Clarke, L.A., Hopwood, J. J., Withers, S. Family 39 a-L-iduronidases and B-D-Xylosidases react through similar glycosylenzyme intermediates: Identification of the human iduronidase nucelophile. Biochemistry, 42, 8054 - 8065, 2003.

Gillet, P.M., Scheiber, R.A., Jevon, G.P/, Israel , D.M., Warshawski, T., Vallance, H., Clarke, L.

Mucopolysaccharidosis type VII (Sly syndrome) presenting as neonatal cholestasis with hepatomegaly. J Ped Gastro Nutri. 33, 216-220., 2001.

Russell, C., Hendson, G., Jevon, G., Matlock, T., Yu, J., Aklujkar, M., Ng, K-Y, and Clarke, L.A. Murine MPS I: Insights into the Pathogenesis of Hurler Syndrome. Clinical Genetics Vol. 53, 349-361, 1998. Russell, C.S., Clarke, L.A. Recombinant proteins for genetic disease. Clin. Genet. 25 t. 55:389-394, 1999.

Clarke L.A., Russell, C.S., Pownall, S., Warrington , C.L., Borowski, A., Dimmick, J.E., Toone, J., Jirik, F.R. Murine Mucopolysaccharidosis Type I: Targeted disruption of the Murine a-L-iduronidase gene. Human Molecular Genetics 4503-511, 1997.

Canadian Society for Clinical Investigation Schering Research Award ($25,000/year) – 1993-1995

B.C. Children’s Hospital Research Foundation Fellowship – 1992-1993

Dr. Elly Hetty – Clinical study coordinator

Karin Yip – Chief technician

Graham Sinclair – Postdoctoral fellow

Derrick Randall – Graduate student