Manifestations of Cardiovascular Disease in Morquio A: Evaluation, Assessment, and Therapy

Morquio A disease is characterized for the build-up of two specific sugars (chondroitin-6- sulfate and keratan sulfate) in all the cells of the body. Many patients with Morquio A suffer from heart disease and it is not clear what the cause of the heart dysfunction is. In this application we would like to get insights on patients’ cardiovascular disease and also we would like to explore the impact of enzyme replacement therapy in heart disease in the Morquio A mouse model.

The outcome of this research will enable us to develop better approaches for treatment strategies that can be applied to other types of MPS.

ISMRD/National MPS Society Partnership Grant

In 2013 the National MPS Society and the International Society for Mannosidosis and Related Diseases (ISMRD) offered a Partnership Grant for mucolipidosis II/III.  The grant is $20,000 for each year of the two years.  Following a global request for proposals which were reviewed by a committee comprised of members of our Scientific Advisory Committee, the grant was awarded December 2013 to Dr. Heather Flanagan-Steet at the Complex Carbohydrate Research Center at the University of Georgia.  We are grateful to Jenny Noble and Mark Stark from ISMRD for their work with the Society, ensuring the success of this endeavor.

“Investigating the role of cathepsin proteases in ML-II cardiac pathology”

Heart valve defects represent a life threatening but poorly understood symptom of ML disease. Recent work in our ML-II zebrafish model has provided new information on why the valves don’t form or function properly. Our earlier work on cartilage defects in this model identified the enzyme, cathepsin K, as a central player in the disease process. Inhibition of cathepsin K in the ML-II background resulted in improved cartilage development, suggesting a new therapeutic strategy for ML disease. Since the development of heart valves and cartilage share many common features, it is likely that cathepsin K also contributes to ML heart valve disease. We propose to use inhibitors of cathepsin K (and another related enzyme cathepsin L) to ask whether they reverse the heart valve defects present in ML-II zebrafish. At least one cathepsin K inhibitor, odanacatib, recently passed Phase III clinical trials for the treatment of osteoporosis and is expected to be available in 2014. Our proposed work may uncover a new opportunity to treat ML valve disease with these inhibitors.

– Adriana Montano, PhD

St. Louis University
St. Louis, MO

AND

Raymond Wang, M.D.
CHOC Children’s Hospital
Orange, CA