Original Article

Gene Therapy (2010) 17, 521–530; doi:10.1038/gt.2009.160; published online 24 December 2009

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

S O Kyosen1,6, S Iizuka1, H Kobayashi1,2,3, T Kimura1,4, T Fukuda5, J Shen1,3, Y Shimada1, H Ida1,2,3, Y Eto1,2,3 and T Ohashi1,2,3

  1. 1Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan
  2. 2Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan
  3. 3Department of Genetic Diseases, The Jikei University School of Medicine, Tokyo, Japan
  4. 4Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
  5. 5Division of Neuropathology, Department of Neuroscience, Research Center of Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan

Correspondence: Dr T Ohashi, Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. E-mail: tohashi@jikei.ac.jp

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

Received 6 May 2009; Revised 17 September 2009; Accepted 19 September 2009; Published online 24 December 2009.

Top

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.

Keywords:

Pompe disease; acid α-glucosidase; lentiviral vector; neonatal gene transfer