The National MPS Society allocated $530,000 in grant funding for 2013, which includes the second year funding for grants awarded in 2012, plus the 2013 grants. The funding the Society provides has been and continues to be critical as we move forward with our mission to find the cures. We received 48 letters of intent from researchers around the world for the six grants offered in 2013. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from 13 researchers.
The Society will also fund $25,000 to support the Lysosomal Disease Network’s NIH grant research goals. The funding is designed for the Neuroimaging Core, which will benefit the four MPS projects. An additional $20,000 will be offered for an ML grant in partnership with ISMRD (International Society for Mannosidosis and Related Diseases). A $10,000 partnership grant with the Ryan Foundation funded the University of MN project “Longitudinal Studies of Brain Structure and Function in MPS Disorders”. The Society also provides funding for post-doctoral fellows to attend the Gordon Conference on lysosomal diseases.
General Grants – two years @ $30,000 each year
Lachlan Smith, PhD
University of Pennsylvania
“Pathogenesis of Bone Disease in Mucopolysaccharidosis Disorders”
Mucopolysaccharidosis (MPS) disorders are genetic diseases that result from deficient activity of enzymes that degrade glycosaminoglycans. Bone disease is prevalent amongst many types of MPS, the consequences of which are particularly severe in the spine, where vertebral abnormalities may lead to spinal cord compression, airway obstruction and deformity. Current systemic treatments for MPS show limited efficacy in correcting spine disease. Our lab has shown that a defining feature of spine disease in across multiple types of MPS is the failure of vertebral bones to calcify normally during growth. This results in the persistence of cartilage in place of bone, and compromises the mechanical stability of the spine. Our overall aim in this study is identify common mechanisms underlying abnormal bone formation across multiple MPS disorders. Using the naturally occurring canine models, we will conduct whole transcriptome next generation screening studies to identify the key regulatory genes that are disrupted in developing MPS bones, and we will directly screen cellular responses to molecules that regulate bone development. Establishing common pathological mechanisms of bone disease across multiple type of MPS will facilitate development of novel treatments that are highly likely to be relevant for many of the 11 enzyme deficiencies of the MPS family of disorders that affect children.
Richard Steet, PhD
University of Georgia
Dr. Dwight Koeberl
“Adjunctive therapy for Hurler syndrome.”
Enzyme replacement therapy (ERT) remains an essential way to treat MPS disease. This therapy works because lysosomal enzymes made in the lab can be taken into cells and delivered to the lysosome with the help of a carbohydrate-dependent receptor. Once in the lysosome, the replaced enzyme helps clear storage. How well this therapy works depends on the ability of the replaced enzyme to efficiently reach and enter certain affected organs like the brain and heart. We propose to use a drug that is already approved by the Federal Drug Administration (FDA) as a means of enhancing delivery of the therapeutic enzyme. We will study how the drug works in MPS cells and then test its ability to improve ERT in a mouse model for MPS-I. Our hope is that this drug, when used in combination with ERT, will not only increase the efficiency of ERT but also lower its cost.
MPS II – two years @ $25,000 each year
Vito Ferro, PhD
University of Queensland
“Development of pharmacological chaperone therapy for MPS II.”
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.
MPS III – two years @ $45,000 each year
Jeffrey Esko, PhD
University of California, San Diego
La Jolla, CA
“Delivery of sulfamidase to the brain.”
MPS IIIA (Sanfilippo A) is a disease in which a key enzyme is missing in cells resulting in the accumulation of a type of complex sugar called a glycosaminoglycan in various tissues. A primary approach for treating related types of disorders involves replacement of the missing enzyme by injection into the circulation. Enzyme replacement therapy resolves many aspects of the disease. Unfortunately, enzyme replacement does not resolve complications of the disease in the central nervous system. This proposal focuses on the development of a novel way to perform enzyme replacement therapy and its application to MPS IIIA, a disease with no current therapeutic options. We show that we can deliver the missing enzyme to cells derived from MPS IIIA patients and that intravenous injection of modified enzyme reduces storage of glycosaminoglycans in a mouse model of MPS IIIA (Sgsh-/-). Furthermore, intranasal administration of modified enzyme demonstrated high levels of delivery to the brain and reduction of pathological glycosaminoglycans. The purpose of this grant is to optimize the transfer of enzyme into the central nervous system in the MPS IIIA mouse. The results will provide the preclinical information needed to proceed towards a novel treatment of the disease in humans.
MPS IVA Grant – two years @ $30,000 each year
Adriana Montano, PhD
St. Louis University
St. Louis, MO
Raymond Wang, M.D.
CHOC Children’s Hospital
“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.