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Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector

Gene Therapy volume 21, pages 427–433 (2014)Cite this article

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Abstract

As both the immune system and the blood–brain barrier (BBB) are likely to be developmentally immature in the perinatal period, neonatal gene transfer may be useful for the treatment of lysosomal storage disease (LSD) with neurological involvements such as metachromatic leukodystrophy (MLD). In this experiment, we examined the feasibility of single-strand adeno-associated viral serotype-9 (ssAAV9)-mediated systemic neonatal gene therapy of MLD mice. ssAAV9 vector expressing human arylsulfatase A (ASA) and green fluorescent protein (GFP) (ssAAV9/ASA) was injected into the jugular vein of newborn MLD mice. High levels of ASA expression were observed in the muscle and heart for at least 15 months. ASA was continuously secreted into plasma without development of antibodies against ASA. Global gene transfer into the brain and spinal cord (SC), across the BBB, and long-term ASA expression in the central nervous system were detected in treated mice. Significant inhibition of the accumulation of sulfatide (Sulf) in the brain and cervical SC was confirmed by Alcian blue staining and biochemical analysis of the Sulf content. In a behavior test, treated mice showed a greater ability to traverse narrow balance beams than untreated mice. These data clearly demonstrate that MLD mice model can be effectively treated through neonatal systemic injection of ssAAV9/ASA.

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Acknowledgements

We thank Dr Volkmar Gieselmann at Rheinische Friedrich-Wilhelms-Universität for kindly providing MLD mice model and Dr James Wilson at the University of Pennsylvania for providing AAV packaging plasmids. This work was supported in part by grants from the Ministry of Health and Welfare of Japan and the Ministry of Education, Science and Culture of Japan.

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  1. Division of Gene Therapy Research, Department of Biochemistry and Molecular Biology, Center for Advanced Medical Technology, Nippon Medical School, Tokyo, Japan

    N Miyake, K Miyake, N Asakawa, M Yamamoto & T Shimada

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  1. N Miyake
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Correspondence to T Shimada.

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Miyake, N., Miyake, K., Asakawa, N. et al. Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector. Gene Ther 21, 427–433 (2014). https://doi.org/10.1038/gt.2014.17

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