2004 Research Grants Gene Therapy for MPS II Dr. Maria Pia Cosma, Telethon Institute of Genetics and Medicine, Naples, Italy Eight human genetic diseases are caused by a deficiency in the enzymatic activity of sulfatases. Among these are five different types of mucopolysaccharidoses (MPS types II, IIIA, IIID, IVA, and VI). The final goal of this project is to develop a gene therapy approach to treat the MPS II (Hunter syndrome) which is due to the deficit of the Iduronate sulfatase (IDS). To this end, we will use a mouse model of MPS II which exhibits many of the characteristics of the human disease. IDS, as well as all the other sulfatases, need to be modified in the cell after they are synthesized in order to be active. We have recently identified SUMF1 gene (Sulfatase Modifying Factor 1), which is responsible for this modification. SUMF1 has a striking enhancing effect on the activity of all sulfatases in cultured cells. To increase our chances of having active IDS in vivo we will deliver both IDS and SUMF1 genes in the MPS II mouse model. The simultaneous delivery of SUMF1 and IDS genes should result in a more effective treatment of MPS II. Ultimately, this protocol could set the stepping stone for the treatment of other MPS due to sulfatase deficiencies. General MPS / ML Grant ?Characterization of the Systemic Inflammatory Response to Lysosomal Storage? Dr. Mark Sands, Washington University School of Medicine, St. Louis, MO Our laboratory is studying several mouse models of lysosomal storage disease that have characteristics similar to the human disease. While we were studying the MPS I mouse, we discovered that the mice have anemia and have difficulty putting on body weight as fat. Our curiosity about this lack of fat led to a variety of new studies. The MPS I mice eat the same and absorb the same amount of nutrients as unaffected mice. MPS I mice also have the same respiration and activity levels as normal mice, thus they have similar metabolic rate. Both the anemia and fat loss could be caused by abnormal inflammatory or immune responses. We therefore looked for inflammation markers in the blood and found an increase in the amount of inflammatory proteins in the affected mice. We are currently determining if the anemia, fat loss, and inflammation are common to other lysosomal storage diseases. Our ultimate goal is to determine what role the inflammatory proteins are playing in lysosomal storage diseases.