The broad long-term goal is to evaluate experimental therapy for lysosomal storage diseases using the murine MPS VII model of beta-glucuronidase deficiency.
The specific aims determine the therapeutic efficacy of bone marrow transplantation (BMT), liver transplantation, retroviral mediated somatic gene transfer, and enzyme replacement therapies. Preliminary results suggested that early and aggressive enzyme replacement therapy is important in neonatal MPS VII mice during rapid development of the skeletal system and central nervous system. Enzyme replacement has the additional apparent advantage of having little risk compared to transplantation and gene transfer therapies. However, other facts to consider are the cost of continued administration of recombinant beta- glucuronidase over long periods of time and the possibility that antibodies to the enzyme or other unexpected side effects could develop in some patients and perhaps decrease the effectiveness of the therapy over time. Therefore, in older individuals there may be advantages to discontinuing enzyme replacement and initiating various forms of long-term transplantation or somatic gene transfer therapies. This project determines the efficacy of these two-step therapeutic approaches in MPS VII mice. All newborns in the study will be given enzyme replacement therapy starting at birth and then will be continued on weekly injections of recombinant enzyme until they are young adults. At this time, some of the mice will be placed on monthly injections of enzyme for long-term maintenance while others will be given either BMT, liver transplantation, or retroviral transduced MPS VII hematopoietic stem cells and enzyme injections discontinued. Comparison of these four therapeutic regimens throughout the normal 2 to 3 year predicted life span of treated MPS VII mice will provide important information useful in developing similar types of therapy for human lysosomal storage diseases. Animal models, such as the MPS VII mouse, are vital for the development of effective and relatively safe forms of therapy for human genetic diseases. Because of the availability of animal models, new and exciting hope has recently been given to children and families which suffer from MPS VII and many other types of inherited disease where product replacement may be of value.
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