Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

• Published in: Gene therapy Vol. 8; no. 17; pp. 1291 - 1298
• Main Authors: DALY, T. M, OHLEMILLER, K. K, ROBERTS, M. S, VOGLER, C. A, SANDS, M. S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.09.2001
• Subjects: Adeno-associated virus; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Animals, Newborn; Applied cell therapy and gene therapy; Auditory system; Biological and medical sciences; Biotechnology; Complications; Deafness - physiopathology; Electroretinography; Evoked Potentials, Auditory, Brain Stem; Expression vectors; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Gene transfer; Genetic Therapy - methods; Glucuronidase - genetics; Health. Pharmaceutical industry; Inborn errors of metabolism; Industrial applications and implications. Economical aspects; Intravenous administration; Medical sciences; Mice; Mice, Mutant Strains; Models, Animal; Mucopolysaccharidosis; mucopolysaccharidosis VII; Mucopolysaccharidosis VII - enzymology; Mucopolysaccharidosis VII - physiopathology; Mucopolysaccharidosis VII - therapy; Neonates; Prevention; Retina - physiopathology; Survival Rate; Transduction, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Animal model; Neonatal; Adenoviridae; Diseases of the osteoarticular system; Mucopolysaccharidosis; Enzymopathy; Carbohydrate; Vector; β-Glucuronidase; Enzyme; Rodentia; Metabolic diseases; Injection; Lysosomal storage disease; Gene expression; Genetic disease; Genetic transfer; Virus; Associated virus; Vertebrata; Phenotype; Mammalia; Mouse; Glycosidases; Hydrolases; O-Glycosidases
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301420

For many inborn errors of metabolism, early treatment is critical to prevent long-term developmental sequelae. We have previously shown that systemic treatment of neonatal mucopolysaccharidosis type VII (MPS VII) mice with recombinant adeno-associated virus (AAV) vectors results in relatively long-term expression of beta-glucuronidase (GUSB) in multiple tissues, and a reduction in lysosomal storage. Here, we demonstrate that therapeutic levels of enzyme persist for at least 1 year following a single intravenous injection of virus in neonatal MPS VII mice. The level and distribution of GUSB expression achieved is sufficient to prevent the development of many aspects of clinical disease over the life of the animal. Following treatment, bone lengths, weights and retinal function were maintained at nearly normal levels throughout the life of the animal. In addition, significant improvements in survival and auditory function were seen in AAV-treated MPS VII mice when compared with untreated mutant siblings. These data suggest that AAV-mediated gene transfer in the neonatal period can lead to prevention of many of the clinical symptoms associated with MPS VII in the murine model of this disease.