2014 Research Grants
The National MPS Society allocated $509,000 in grant funding for 2014 which includes the second year funding for grants awarded in 2013, the unspent MPS III funds from 2012 and the 2014 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 20 letters of intent from researchers around the world for the General, MPS II, MPS IVA and MPS VI grants. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from 8 researchers.
The Board of Directors allocated $100,000 to Abeona Therapeutics which has licensed the MPS IIIA and MPS IIIB gene therapy technology from Nationwide Children’s Hospital. Funds already raised by Abeona have been funneled to Nationwide for MPS III drug manufacturing and preclinical research plus two INDs (investigational new drug applications). The financial distribution from the Society will help move the clinical trial forward.
The Society also provided $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 $8,000 was 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 funds 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 American Society and Gene and Cell Therapy conference.
Moin Vera, MD, PhD
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
“The role of angiotensin II-mediated inflammation in MPS I vascular disease: a study of pathophysiologic mechanism and evaluation of angiotensin receptor blockade therapy”
Bones, joints and cardiovascular tissues are among the most difficult to treat with the standard therapies available today for MPS I. Disease affecting these tissues also causes the most disability in our patients, including poor quality of life and risk of early death. Inflammation is a mechanism that seems to explain much of the bone and joint disease in animal models of mucopolysaccharidoses. In this project, we are studying a specific inflammatory pathway in vascular disease, which also occurs in MPS patients. This alternative inflammatory pathway is hypothesized to be stimulated by angiotensin II, a molecule that plays a role in
atherosclerosis and coronary artery disease. We plan to test the importance of this pathway by studying vascular smooth muscle cells from MPS I mice and we plan to test a treatment for this type of inflammation using an angiotensin receptor blocker in MPS I mice.
R. Scott McIvor, PhD
University of Minnesota
“AAV mediated gene transfer to the CNS for MPS II”
Currently there is no established treatment for neurologic symptoms of Hunter syndrome, causedabsence of the enzyme iduronate sulfatase (IDS). We have established conditions for effective gene transfer to all areas of the brain using a genetically engineered virus (AAV). In this research project, we will test these conditions for introduction of the gene for IDS into the brain in mice that are deficient in IDS, then testing for prevention of neurologic disease. We anticipate that results from these studies will facilitate the development of genetic therapy for neurologic symptoms of Hunter syndrome.
Beverly Davidson, PhD
The Children’s Hospital of Philadelphia
“Overcoming limitations inherent in sulfamidase to improve MPS IIIA gene therapy”
Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disease caused by the deficiency of sulfamidase. MPS IIIA is characterized by progressive neurodegeneration accompanied by loss of social skills and aggressive behavior, hyperactivity and sleep disturbance. Somatic features are often mild and variable. To correct the brain pathology in lysosomal storage diseases, our group and others have successfully introduced genes encoding the missing enzymes into brain. The basis of this gene therapy method lies in the efficient
secretion of lysosomal enzymes. If the enzyme was effectively secreted from gene corrected cells, then it could be uptaken by the nearby cells, and broad correction in the brain could be achieved. In our unpublished work, we find that the how well lysosomal enzymes are secreted vary greatly. In this work, we propose to use genetic methods to modify sulfamidase to improve secretion and temper degradation to provide for greater therapeutic benefit.
Calogera Simonaro, PhD
Icahn School of Medicine at Mount Sinai
New York, NY
“Pentosan Polysulfate and GAGs in MPS”
We have previously shown that glycosaminoglycan (GAG) storage in the mucopolysaccharidoses (MPS) leads to inflammation, a major contributor to the degenerative cartilage disease in MPS patients. We have also recently identified one FDA-approved drug, pentosan polysulfate (PPS), which resulted in remarkable clinical improvements in MPS VI rats. We compared the effect of oral, daily PPS administration to once weekly, subcutaneous (sc) injection in this animal model. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Enhanced effects of sc treatment included greater endurance, better improvements in cartilage and bone and, most importantly, GAG reduction in urine, serum and tissues. Treating MPS patients with PPS is medically plausible given that the drug has been safely used in patients with other conditions for many years, and it addresses two key pathologic features – GAG storage and GAG-induced inflammation. The first clinical trial of PPS in MPS will begin this summer. However, despite these advances, the mechanism(s) leading to PPS-induced GAG reduction in MPS remainunknown, nor is it known if the findings in MPS VI extend to other MPS types. The current proposal is therefore focused on addressing these important questions.