Grants Awarded in 2005 The National MPS Society has awarded $320,000 in new grants for 2005-2006. Two grants for MPS III research were awarded $60,000 each, $30,000 for each of the 2 years of funding. This year a special grant category was created for research specific to Bone and Joint research, and those researchers will receive $50,000 for each of the 2 years of funding, for a total per grant of $100,000. The MPS II research grant offered this year will not be funded due to the lack of acceptable proposals received. Dr. Matthew Ellinwood, Iowa State University, Department of Animal Science Ames, IA . "Therapy for MPS IIIB: Naglu Targeting to the CNS" The blood brain barrier is the single greatest hurdle to bringing therapies for neuropathic lysosomal storage diseases to clinical application. One approach to overcome this barrier involves direct injection into the central nervous system of either recombinant enzyme, gene therapy vectors, stem cells, or gene therapy treated stem cells. An alternate method is to genetically engineer the missing enzyme of a particular lysosomal storage disease, so that it is able to cross the blood brain barrier by an active process of uptake from the blood and delivery across the blood brain barrier. This would allow for treatment of the central nervous system either by intravenous delivery of the engineered recombinant enzyme, or alternatively, treatment with a liver directed gene therapy vector designed to deliver the gene for the engineered enzyme. We propose to evaluate this latter method to develop a treatment for mucopolysaccharidosis type IIIB (MPS IIIB). Using parts of proteins that bind the LDL receptor we propose to genetically engineer the Naglu enzyme so that it will cross the blood brain barrier via this receptor system. We will evaluate this method n a cell culture system, and successfully engineered enzyme will then be evaluated clinically using liver directed gene transfer into the murine and canine models of MPS IIIB. Dr. Donald Anson, Department of Genetic Medicine, North Adelaide, South Australia, Australia "Lentiviral-mediated Gene therapy for MPS IIIA" Gene therapy is an attractive option for the treatment of the mucopolysaccharidosis (MPS) including MPS III. The development of a new generation of technologies for the delivery of genes has meant that gene therapy now looks a more realistic option than ever before. However, the safety and efficacy of these technologies need to be carefully evaluated before clinical application can be considered, and even with these new vectors, treatment of brain pathology is challenging. This project aims to use a small animal (mouse) model of one of the most common MPS, MPS III A, to evaluate a new gene delivery technology for its ability to treat brain pathology. Two methods for delivering the vector to the bran will be evaluated. The level and distribution of gene delivery that results, its persistence, and its effect on disease pathology, will be assessed using a variety of enzymatic, molecular and biological techniques. Dr. Calogera Simonaro, Mt. Sinai School of Medicine, New York, NY 10029 "Pathogenesis and Treatment of Bone and Joint Disease in the Mucopolysaccharidoses" The overall goal of our work is to use animal models of the mucopolysaccharidoses (MPS) to investigate the underlying causes(s) of cartilage and bone disease in these disorders. We have already shown that the cells in MPS cartilage are prone to death, and that in response to this primary damage, a series of biochemical changes occur (known as ?inflammation?), exacerbating the disease. We will continue to evaluate the causes(s) of MPS bone and joint disease, and based on these results, identify new ways to monitor disease severity, progression and treatment response. We will also evaluate new approaches to therapy. We will extend our findings in the cartilage of MPS animals to other joint tissues and bone. We will assess cell death and ?inflammation? in these tissues, as well as study bone growth. We will also utilize findings from these studies to identify specific ?biomarkers? that might predict disease severity and treatment response. For this we will study these markers in the blood and joints of MPS VI animals treated by enzyme replacement and gene therapy. Lastly, we will use MPS animal models to evaluate new approaches to treat these disorders, including using inhibitors of ?inflammation? and/or cell death, as well as enzyme replacement therapy using a new form of the recombinant enzyme that can penetrate cartilage more efficiently. Dr. Sharon Byers, Department of Genetic Medicine, North Adelaide, South Australia, Australia "The Pathogenesis of Cartilage Degradation in MPS VI" Cartilage/joint disease presents a significant challenge to the clinical care of patients with mucopolysaccharidosis (MPS). With the advent of enzyme replacement therapy (ERT), the injection of enzyme into the circulation and into the localized joint space has the potential to significantly alter the progression of cartilage disease in MPS. However, to maximize the benefit of ERT it must be applied prior to the start of clinical symptoms. The benefit of ERT to patients with established symptoms is less clear cut. The pathogenesis of cartilage destruction in MPS I is poorly understood although it appears to resemble that observed in osteoarthritis (OA). In particular the turnover of the glycosaminoglycan (GAG) component of MPS cartilage and the relationship between GAG storage and disease progression is unclear. The focus of this proposal is to understand the mechanism of cartilage destruction in MPS, using the MPS VI cat model. The degradation of cartilage proteoglycans and the subsequent uptake and storage of their GAG component will be investigated. This information will be used to develop supplemental therapies targeted to joint disease in MPS.