Abstract
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 β-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.
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Acknowledgements
This work was supported in part by NIH grants DK53920 (MSS) and HD35671 (MSS, CAV), the National MPS Society Raymond Bryan IV Fellowship (TMD), the Spencer T and Anna W Olin Foundation (KKO) and the Edward Mallinckrodt Jr Foundation (KKO). Stocks of recombinant AAV were produced at the Gene Therapy Center of the University of Florida, and supported by NIH grants HL59412 and P01NS36302 to Dr Nicholas Muzyczka. All animal procedures were approved and performed in accordance with the guidelines established by the Institutional Animal Care and Use Committee of Washington University.
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Daly, T., Ohlemiller, K., Roberts, M. et al. Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Ther 8, 1291–1298 (2001). https://doi.org/10.1038/sj.gt.3301420
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DOI: https://doi.org/10.1038/sj.gt.3301420
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