PubMed2000
Neurodegenerative diseases caused by lysosomal enzyme deficiencies are catastrophic illnesses with both peripheral organ and central nervous system abnormalities. The mucopolysaccharidosis type VII mouse with beta-glucuronidase deficiency was used to develop an alternate approach to gene therapy, in which a "universal" cell line engineered to secrete the missing enzyme is implanted directly into all recipients requiring the same enzyme replacement. The cells, though nonautologous, were rendered immunologically tolerable by protection in immunoisolating microcapsules. Since the blood-brain barrier impedes the passage of large molecules such as beta-glucuronidase, encapsulated cells producing beta-glucuronidase were introduced directly into the lateral ventricles of the brain. Based on this strategy, beta-glucuronidase was delivered throughout most of the central nervous system, reversing the histological pathology and reducing the previously elevated levels of lysosomal enzymes beta-hexosaminidase and alpha-galactosidase. The effectiveness of this approach was further demonstrated with improvements in the mutant circadian rhythm behavioral abnormalities. Compared to wild-type and heterozygous mice, the mutant mice had an unstable periodicity, fragmented activity, and a sixfold reduction in wheel running activity. After treatment, the mutant behavioral abnormalities were significantly improved with a more stable periodicity and a less fragmented pattern of activity. While the overall total activity level did not increase in the treated mutants, it did not show the deterioration observed in the sham-treated as well as in the untreated mutant mice. Hence, this alternative cell-based gene therapy demonstrates biochemical, histological, and behavioral efficacy and provides a potentially cost-effective and nonviral treatment applicable to all lysosomal storage diseases with neurological deficits.