During the initial funding period we observed adipose storage deficiency, anemia and muscle wasting in several murine models of LSD. We have also shown that circulating levels of pro-inflammatory molecules are significantly increased. It is known that chronic inflammation can result in the clinical signs listed above. Therefore, we hypothesize that chronic inflammation contributes to the systemic disease phenotype in LSDs. Inflammation has also been observed in the CNS of several LSDs. We have preliminary data suggesting that inhibiting the inflammatory response in conjunction with viral vector-mediated enzyme replacement is more effective that either therapy alone. A more thorough understanding of this inflammatory process and how to inhibit it may reveal new therapeutic targets or strategies. During an AAV-mediated gene therapy study in MPS VII mice, we noted a high frequency (30-50%) of hepatic tumors in the older treated mice. We have since repeated this initial observation and are proposing to determine the causative agent responsible for this disturbing finding. We will accomplish the goals of this proposal with the following specific aims: 1) We will determine the underlying cause of the adipose deficiency, muscle wasting and anemia observed in several different models of lysosomal storage disease. In this specific aim we will test the hypothesis that chronic inflammation is associated with lysosomal storage disease and contributes to both the cachectic phenotype and anemia. 2) We will determine the efficacy of CNS-directed gene therapy coupled with anti-inflammatory therapy in the murine model of globoid-cell leukodystrophy. In this specific aim we will test the hypothesis that gene replacement therapy will synergize with anti-inflammatory therapy to increase the efficacy in this neurodegenerative LSD. 3) We will determine the cause of the tumor development observed in the MPS VII mice injected intravenously at birth with a recombinant AAV vector. In this specific aim we will test the hypotheses that the AAV vector, GUSB protein or GUSB enzyme activity causes the development of hepatic tumors after systemic AAV-mediated gene therapy.
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