Evaluation of Pathological Manifestations of Disease in Mucopolysaccharidosis VII Mice after Neonatal Hepatic Gene Therapy
| Autor: | Lingfei Xu, Mark E. Haskins, N. Matthew Ellinwood, Katherine P. Ponder, Robert L Mango, Mark S. Sands |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Mucopolysaccharidosis Genetic enhancement Genetic Vectors Spleen Mucopolysaccharidosis VII Thymus Gland Biology Eye Mice 03 medical and health sciences Dogs 0302 clinical medicine Transduction Genetic Internal medicine Intestine Small Drug Discovery medicine Lysosomal storage disease Genetics Animals RNA Messenger Lung Molecular Biology Aorta Glucuronidase Glycosaminoglycans 030304 developmental biology Pharmacology 0303 health sciences Kidney Myocardium Brain Genetic Therapy medicine.disease Small intestine Enzyme assay 3. Good health medicine.anatomical_structure Endocrinology Animals Newborn Liver Organ Specificity 030220 oncology & carcinogenesis Immunology biology.protein Molecular Medicine |
| Zdroj: | Molecular Therapy. 6(6):745-758 |
| ISSN: | 1525-0016 |
| DOI: | 10.1006/mthe.2002.0809 |
| Popis: | Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by beta-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits. |
| Databáze: | OpenAIRE |
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