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Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction

Gene Therapy volume 17, pages 521–530 (2010)Cite this article

Abstract

Pompe disease results from the deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to accumulated glycogen in the heart and the skeletal muscles, which causes cardiomyopathy and muscle weakness. In this study, we tested the feasibility of gene therapy for Pompe disease using a lentivirus vector (LV). Newborn GAA knockout mice were treated with intravenous injection of LV encoding human GAA (hGAA) through the facial superficial temporal vein. The transgene expression in the tissues was analyzed up to 24 weeks after treatment. Our results showed that the recombinant LV was efficient not only in increasing the GAA activity in tissues but also in decreasing their glycogen content. The examination of histological sections showed clearence of the glycogen storage in skeletal and cardiac muscles 16 and 24 weeks after a single vector injection. Levels of expressed hGAA could be detected in serum of treated animals until 24 weeks. No significant immune reaction to transgene was detected in most treated animals. Therefore, we show that LV-mediated delivery system was effective in correcting the biochemical abnormalities and that this gene transfer system might be suitable for further studies on delivering GAA to Pompe disease mouse models.

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Acknowledgements

We acknowledge Dr Y-T Chen (Department of Pediatrics, Duke University Medical Center, Durham, NC, USA) for providing the GAA cDNA, Dr N Kasahara (Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA) for the generating lentiviral system, Dr N Raben (Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, Bethesda, MD, USA) for the Gaa−/− mice and the Genzyme Corporation for monoclonal anti-GAA antibodies. We also would like to express our thanks to our colleagues of the Department of Gene Therapy and to the staff of the Animal Facilities Division. Dr Kyosen was supported by a research fellowship from the Japan International Cooperation Agency (JICA) and the Uehara Foundation, Japan. This research was supported by The Jikei University Research Fund, received grants for The Research on Measures for Intractable Diseases, Japanese Ministry of Health Welfare and Labor, from Japan International Cooperation Agency (JICA) and Uehara Foundation-Japan.

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  1. S O Kyosen

    Present address: 6Current address: Centro de Referência em Erros Inatos do Metabolismo (CREIM), Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil,

Authors and Affiliations

  1. Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan

    S O Kyosen, S Iizuka, H Kobayashi, T Kimura, J Shen, Y Shimada, H Ida, Y Eto & T Ohashi

  2. Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan

    H Kobayashi, H Ida, Y Eto & T Ohashi

  3. Department of Genetic Diseases, The Jikei University School of Medicine, Tokyo, Japan

    H Kobayashi, J Shen, H Ida, Y Eto & T Ohashi

  4. Department of Urology, The Jikei University School of Medicine, Tokyo, Japan

    T Kimura

  5. Division of Neuropathology, Department of Neuroscience, Research Center of Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

    T Fukuda

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  1. S O Kyosen
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The department of Genetic Diseases of the Jikei University School of Medicine receives grants from the Genzyme Corporation.

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Kyosen, S., Iizuka, S., Kobayashi, H. et al. Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction. Gene Ther 17, 521–530 (2010). https://doi.org/10.1038/gt.2009.160

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