ISSN:
1573-2665
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Lysosomal storage diseases (LSD) are considered to be appropriate disorders for gene therapy/cell therapy. We are attempting to treat one of these disorders using a mouse model, the Sly mouse. This is an authentic model for human β-glucuronidase deficiency, MPS VII. We have carried out two types of experimental protocols; in vivo gene therapy and ex vivo gene therapy using Sly mice. For in vivo gene therapy, we produced a recombinant adenovirus that expresses human β-glucuronidase and administered this to Sly mice intravenously. The β-glucuronidase activities in liver and spleen were elevated to 40% and 20%, respectively, of the heterozygote enzyme level at day 16. Expression persisted for at least 35 days. Pathological abnormalities improved in these tissues and urinary glycosaminoglycan excretion was reduced in treated animals. ex vivo gene therapy/cell therapy was carried out using macrophages obtained by cultivation of bone marrow cells. Non-myeloablated macrophages from normal mice were transplanted into Sly mice, and after 7 days donor cells had populated the liver and spleen. The human β-glucuronidase (HBG) activity was increased in liver and spleen, although these enzyme activities subsequently fell by 38 days. The pathological improvement in Sly mice was evident at day 38 post transplantation. Furthermore, the macrophages from Sly mice were treated with retrovirus/adenovirus vector expressing HBG activity and the glycosaminoglycan accumulation was markedly decreased after 5 weeks. These data suggest that genetically engineered macrophage transplantation may be a very useful form of ex vivo gene therapy for lysosomal storage diseases. We also discuss the possible treatment of the CNS involvement in lysosomal storage diseases by gene therapy/cell therapy.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1005692215317
Permalink
