Immuno-isolation gene therapy for a lysosomal storage disease

Lysosomal enzyme deficiencies are potentially catastrophic, genetic diseases. We used the beta-glucuronidase deficient mouse model of mucopolysaccharidosis type VII (MPS VII) to develop an alternate approach to therapy. A "universal" cell line engineered to secrete the missing enzyme was implanted in recipients requiring the enzyme replacement. The cells, though non-autologous, were rendered immunologically tolerant by alginate microencapsulation to provide protection from immune mediators. Using this immuno-isolation gene therapy strategy, the microcapsule formulation was optimized for beta-glucuronidase delivery to the peripheral organs of MPS VII mice from intraperitoneally implanted microcapsules. However, the results of this experiment revealed three primary obstacles to be overcome: the mice developed an immune response against the re-supplied mouse beta-glucuronidase, the treatment did not address the early onset of the disease, and beta-glucuronidase was unable to cross the blood-brain barrier into the central nervous system (CNS) to treat the neurodegeneration of this disease. The anti-beta-glucuronidase immune response was transiently overcome using immunosuppression. To address the early disease onset, neonatal MPS VII mice were implanted within days of birth. Neonatal treatment delayed the onset of disease; however, the eventual development of antibodies limited the duration of the treatment. To address the third problem of gene product delivery to the CNS, small microcapsules were optimized for implantation into the rodent CNS and studied in vivo. Subsequently, microcapsules secreting beta-glucuronidase were implanted into the CNS of MPS VII mice. This treatment reduced biochemical and histological disease parameters and improved behavior as assessed by circadian rhythm analyses. A combined peripheral and CNS treatment normalized the lysosomal storage throughout the peripheral organs and much of the CNS, an achievement not attained by other treatments of adult MPS VII mice. This novel cell-based immuno-isolation gene therapy demonstrates a potentially cost-effective and non-viral treatment alternative applicable to both peripheral and neurodegenerative lysosomal storage diseases.