Grants Awarded in 2006 The National MPS Society has awarded $290,000 in new grants for 2006. One grant for MPS II and two grants for general MPS and Related Disease research were awarded. Each grant is for a total of $80,000, $40,000 for each of the two years of funding. An additional $50,000 was awarded to Dr. Brooks to further facilitate his work in MPS III with chaperone therapy. Dr. Joseph Muenzer was awarded $120,000 in February, 2006 for his work "AAV Gene Therapy for Mucopolysaccharidosis II". Dr. Muenzer will receive $60,000 for each of the two years of funding. Funding for this grant is from an MPS II grant not awarded in 2005 plus additional MPS II research dollars received in 2005. "AAV Gene Therapy for Mucopolysaccharidosis II" Dr. Joseph Muenzer, University of North Carolina, Chapel Hill, NC The focus of our laboratory is to develop new treatments for patients with MPS disorders. A mouse model for MPS II (Hunter syndrome) was created in the laboratory to develop gene therapy procedures to treat both the physical and the central nervous system involvement. The goal of gene therapy in MPS II is to replace the abnormal gene (iduronate sulfatase) by introducing a normal copy into cells. Modified viruses can be used to deliver genetic material into cells. We have created a delivery system using an adeno-associated virus (AAV) which contains a normal copy of the gene altered in MPS II. Our research has shown correction of the liver storage of glycosaminoglycans in MPS II mice after IV administration of these viruses. This research proposal is to expand our studies in MPS II mice to characterize the extent of correction in other tissues and to use newer viruses that may allow better expression of iduronate sulfatase thereby improving the effectiveness of MPS II gene therapy. The successful completion of these studies will generate the animal data needed to submit an application for a human gene therapy clinical trial in MPS II patients. "AAV-Mediated Gene Therapy of the Hunter Syndrome in the MPS II Mouse Model" Dr. Maria Pia Cosma, TIGEM, Naples, Italy Children affected by mucopolysaccharidosis type II (MPS II: Hunter syndrome) lack the activity of the iduronate 2-sulfatase enzyme (IDS). They accumulate compounds in their body that gradually kill their cells and damage all of their visceral organs. At present, efficient cures are not available. A gene therapy approach was initiated to treat this disease in a mouse model of MPSII. The affected mice were injected with viral particles that targeted the liver. High levels of active IDS was produced and secreted into their plasma and taken up by all of the organs. This approach gave important results, as the mice were cured of their visceral defects. Now we plan to dissect carefully the brain defects in the MPSII mouse model. We have already generated data showing that we can deliver the IDS enzyme in the brain after systemic treatment of the MPSII mice. We now aim to design an efficient gene therapy approach to cure the brain defects in the mice thought direct deliver of the viral particles in the cerebrospinal fluid. Finally, our aim is to treat baby MPSII mice. Their liver and muscle will be modified to produce and secrete high amounts of active IDS into the blood, which can again cross-correct the other damaged organs. If successful, this approach should allow the treatment of the disease at a very early stage, and even before the symptoms are manifested. "Development of a Therapeutic Bone-Targeting System for MPS" Dr. Shunji Tomatsu, St. Louis University, St. Louis, MO The long term goal of this research is to establish a bone-targeting system for enzyme replacement therapy to improve the bone lesions present in the mucopolysaccharidoses (MPS). Current approaches for the treatment of MPS have little or no impact correcting the bone pathology. In this proposal, we will test a newly designed drug delivery system to target bone using an acidic amino acid oligopeptide as a carrier. Modifying the enzyme will allow it to be delivered to the bone more specifically and will enhance the drug effectiveness and reduce the side effects. The enzymes that are deficient in MPS will be tagged with the small acid peptide. The tagged enzymes will be tested on MPS mice models, initially MPS IVA, to evaluate whether it is more effectively delivered to the bone lesions compared to the untagged enzymes. By infusing the deficient enzymes into MPS IVA mouse models weekly for a long term, we can see how effectively they treat the disease and obtain helpful information required to design future human trials possibly applicable to all MPS diseases in which patients suffer from bone lesions. We are currently aiming at the human clinical trial on MPS IVA based upon the result. "Evaluation of Enzyme Enhancement Therapy forMucopolysaccharidosis Type IIIA" Dr. Doug Brooks, Children, Youth and Women's Health Services, Adelaide, Australia Genetic diseases are a fundamental cause of human suffering, depriving many children (up to 2.5% of births) and some adults of a normal existence. Lysosomal storage disorders (LSD) are a group of over 45 different genetic disorders, each involving a defect in lysosomal function. Mucopolysaccharidosis III A (MPS III A) is an LSD that affects mainly children, but also some adults and can result in very severe brain disease. MPS II A is caused by a defect in an enzyme called sulphamidase. We plan to develop a new therapy, which will involve stabilising the patient's mutant sulphamidase protein, to increase the level of enzyme activity and treat the disease. We will test various chemical compounds for their ability to increase the level of sulphamidase enzyme activity in patient cells. The project will potentially lead to the development of a safe, non-invasive therapy to treat this severe disorder.