Behavioral consequences of bone marrow transplantation in the treatment of murine mucopolysaccharidosis type VII.

The gusmps/gusmps mouse is a model of the human lysosomal storage disease mucopolysaccharidosis type VII caused by deficient beta-glucuronidase activity. Bone marrow transplantation has been shown to correct some of their biochemical and pathological abnormalities but its efficacy in correcting their neurological functional deficits is unknown. We transplanted the neonatal gusmps/gusmps mice and their normal controls and evaluated their central nervous system function with two behavioral tests: the grooming test, a developmentally regulated and genetically based activity, and a Morris water maze test which assessed spatial learning abilities. The two transplanted groups groomed less than the normals, were unable to remember the location of an invisible platform from day to day, and were severely impaired at developing strategies to locate the platform in unfamiliar locations. The performance of both normal and mutant transplanted groups was clearly inferior to the untreated normals and, in some instances, close to or worse than the untreated mutants, even though the enzyme abnormalities of the mutants have been partially corrected. Hence, the behavioral deficits in the mutant mice were not restored to normal while similarly treated normal mice showed significant functional deterioration, indicating the detrimental consequence of this therapy in the neonatal period.

Treatment of a lysosomal storage disease, mucopolysaccharidosis VII, with microencapsulated recombinant cells.

Most lysosomal enzyme deficiencies are catastrophic illnesses with no generally available treatments. We have used the beta-glucuronidase-deficient mouse model of mucopolysaccharidosis type VII (MPS VII) to develop an alternative approach to therapy. A "universal" cell line engineered to secrete the missing enzyme is implanted in all recipients requiring the same enzyme replacement. The cells, although nonautologous, are rendered immunologically tolerant by encapsulation in microcapsules that provide protection from immune mediators. Using this strategy, we injected beta-glucuronidase-secreting fibroblasts enclosed in alginate microcapsules into mutant MPS VII mice. After 24 hr, beta-glucuronidase activity was detected in the plasma, reaching 66% of physiological levels by 2 weeks postimplantation. Significant beta-glucuronidase activity was detected in liver and spleen for the duration of the 8-week experiment. Concomitantly, the intralysosomal accumulation of undegraded glycosaminoglycans was dramatically reduced in liver and spleen tissue sections and urinary glycosaminoglycan content was reduced to normal levels. Elevated secondary lysosomal enzymes beta-hexosaminidase and alpha-galactosidase were also reduced. However, implanted mutant MPS VII mice developed antibodies against the murine beta-glucuronidase, demonstrating a potential obstacle in patients with a null mutation who react against the replaced enzyme as a foreign antigen. The antibody response was transiently circumvented with a single treatment of purified anti-CD4 antibody coadministered with the microcapsules. This resulted in increased levels and duration of beta-glucuronidase delivery. Similarly, treated heterozygous mice maintained elevated levels of beta-glucuronidase and did not develop antibodies. This novel cell-based therapy demonstrates a potentially cost-effective and nonviral treatment applicable to all lysosomal storage diseases.