2003 Research Grants The National MPS Society awarded seven research grants for 2003. Each grant is for $30,000/year for two years. Funding for the grants was provided by the generous donations of our members for syndrome specific research and also by the money raised by the 2002 walk/runs. We are very grateful to the R. A. Bryan Foundation for funding one of the MPS III grants. Twenty-one proposals were received, including 6 for MPS I and 12 for MPS III. We regret that no proposals were received for MPS II, so that grant will not be funded in 2003. Members of our Scientific Advisory Board reviewed the proposals; the final determination of funding was made by the Board of Directors. "SB (Sleeping Beauty) Transposon-mediated Gene Therapy for MPS I" Dr. Elena Aronovich, Pediatrics and Institute of Human Genetics, University of Minnesota, Minneapolis, MN The Sleeping Beauty transposon, a novel, non-viral integrating system for gene transfer, will be tested as a tool for gene therapy of mucopolysaccharidosis type I. Our preliminary data obtained with an MPS VII mouse model indicate the feasibility of this approach. Using the transposon for expression of b-glucuronidase, we achieved enzyme levels that were sufficient to reverse lysosomal pathology in adult mouse livers in a 2-month experiment. Here, we propose to construct therapeutic transposon vectors carrying a human a-L-iduronidase gene that will be injected intravenously into MPS I mice. Correction of a-L-iduronidase enzyme deficiency and lysosomal pathology will be evaluated in mouse livers in a long-term (4 months) study. The biodistribution of the therapeutic transposon will be also determined. The proposed experiments will lay groundwork for future application of SB-mediated gene transfer to treatment of MPS diseases in human patients. "Intravitreol Gene Therapy in III B Mice" Dr. Judith Ogilvie, Ophthalmology & Visual Services, Washington University, St. Louis, MO Mucopolysaccharidoses (MPS) are progressive diseases usually resulting from genetic defects in one of the lysosomal enzymes. Treating the eyes of adult MPS VII mice with virus-mediated gene therapy reduces lysosomal storage in treated eyes and in some parts of the brain. However, the severe systemic disease complicates accurate functional testing. Determining how much function can be recovered after treating established lysosomal storage in the nervous system is important, because most individuals with these diseases are diagnosed only after they begin to show symptoms. This proposal's goals are to examine whether intravitreal gene therapy improves vision function in MPS IIIB mice, and to lay the groundwork for future studies testing higher brain function. These mice have well-characterized pathology in their eyes and brains. Their longer life-span allows us to follow expression of the therapeutic enzyme longer than in MPS VII mice. Furthermore, this study will show whether transport from the eye into the brain works with a different lysosomal enzyme. Finally, since MPS III diseases predominantly affect the nervous system with mild systemic complications, behavioral tests can be performed at later ages. The proposed studies will provide the necessary preliminary information for designing cognitive function experiments in MPS IIIB mice. "Gene Therapy in Canine MPS III-B" Dr. Philippe Moullier and Matthew Ellinwood, Laboratoire de Therapie Genique, Nantes Cedex, France The focus of this work is the further development of the canine model of MPS IIIB with an emphasis on gene therapy. 1) We propose to treat affected dogs at birth intravenously with gene therapy vectors to evaluate the ability of the normal gene to produce enzyme that is capable of being secreted into the blood and cross correct cells in other parts of the body. While this approach may not directly address the serious issues of brain disease in MPS IIIB, it provides important information about whether the gene is capable of producing normal enzyme that can be taken up by other cells. This is critical information, necessary for effective gene therapy to treat the brain disease seen in MPS IIIB. 2) We will evaluate gene therapy to the brain, via the direct injection of gene therapy vectors or stem cells. 3) Concurrent with these projects will be the continued study of the canine model, with an emphasis on identifying signs of disease that will help evaluation therapy. "Inhibition of GAG Synthesis as a Therapy for MPS IVA and VI" Dr. Sharon Byers, Women's and Children's Hospital, North Adelaide, Australia MPS disorders arise from a deficiency in an enzyme required for the degradation of complex carbohydrate molecules. Children with MPS display symptoms that include but are not limited to reduced height, blindness and brain pathology. Multi-tissue treatment for MPS is the subject of intensive research and centres around increasing the amount of deficient enzyme through enzyme replacement therapy (ERT), bone marrow transplantation or gene therapy. ERT in particular has shown great promise and has reached clinical trial for several MPS. However, some tissues with limited access to the circulation are not amenable to intravenous ERT. These include the brain, cornea and cartilage. Current therapy protocols thus do not address all sites of pathology. In this project therapy will be approached from a different direction. The synthesis of the complex carbohydrate substrate normally degraded by the deficient enzyme will be reduced to a level that more closely matches the reduced enzyme activity observed in MPS patients, this concept is termed substrate deprivation therapy. Small sugar analogues of glucose and galactose will be synthesized and assessed for their ability to inhibit carbohydrate synthesis. The advantage of this type of therapy is that the inhibitors will equilibrate with cellular pools of carbohydrate throughout the body. All sites of pathology in MPS are thus amenable to substrate deprivation therapy. "Joint and Bone Disease in MPS VI" Dr. Calogera Simonaro, Mr. Sinai School of Medicine, New York, NY This grant proposal will study joint and bone disease in animals with mucopolysaccharidosis (MPS) type VI (Maroteaux-Lamy disease). Our goal is to gain a better understanding of this disorder and to develop new and/or improved therapies. We will specifically study the mechanism(s) causing cell death in cartilage and bone, and the role of inflammation in the disease process. We will also examine enzyme therapy and other therapeutic strategies for these conditions. It is our hope that these studies on animal models of MPS VI will lead to more effective therapy for this and other MPS disorders, particularly in the joints and bones. "Pathological and Molecular Characterization of Feline Mucolipidosis II - First Model of Human I-Cell" Dr. Urs Giger, Medical Genetics, University of Pennsylvania, Philadelphia, PA Mucolipidosis II (ML II), also called I-cell disease, is a unique cellular storage disease leading to severe skeletal malformations, growth and mental retardation, and death within the first decade of life. Although ML II is caused by faulty trafficing of enzymes to reach cellular organelles (lysosomes), it shares many clinical features of the more common forms of mucopolysaccharidoses (MPS). We have established a colony of domestic shorthair cats with naturally-occurring ML II, the first model in which to study this rare storage disease. After we documented the clinical features in cats and mode of inheritance, we propose now to characterize the pathology of ML II in tissues from affected cats and compare the results to the scant information from human patients. Although the deficient enzyme has been identified, the molecular basis remains unknown in affected cats as well as humans. We therefore also propose to characterize feline I-cell disease at the molecular genetic level by sequencing the gene of the normal enzyme and identify the disease-causing mutation in affected cats. Thereby, the knowledge gained in feline ML II will likely further our understanding of this disease in humans and provides the necessary characterization for this animal model to become useful in the development and assessment of the safety and efficacy of novel therapeutic interventions. Dr. Elsa Shapiro awarded MPS Research Grant Occasionally the MPS Sociey receives requests for grant funding outside our normal funding cycle. The year we received 2 excellent proposals, and the Board of Directors chose to award a one year grant of $8750 to Dr. Elsa Shapiro at the University of Minnesota for the fellowship of Dr. Kendra Bjoraker. This grant was possible because not all the money allocated for the Partnership Grant was requested. "Research Training in Psychosocial Development and Quality of Life in MPS Disorders". Dr. Elsa Shapiro, University of Minnesota, Minneapolis, MN Few psychologists have expertise in MPS disorders. As a result, little research has been done on the factors that contribute to quality-of-life and psychosocial outcomes of children with MPS. We need to determine how new treatments (such as enzyme replacement or gene therapies) as well as established therapies such as bone marrow and cord blood transplant might alter quality-of-life and psychosocial status as well as the previously studied cognitive and language development. Also, this will enable us to find ways to improve the quality-of-life and psychosocial outcomes of these children. We propose to develop a training program at the University of Minnesota to train a neuropsychologist to carry out such research to increase understanding of MPS. We have developed a detailed program curriculum. We are uniquely able to carry out training at Minnesota due to the number of physicians and psychologists here who can provide expert mentorship. In addition to training in the disciplines necessary to carry out this research, the trainee would carry out such a study during the year's work. We hope that training such a person would be a model for other centers to pursue such research and training and would lead to federal funding.