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Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits

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Journal of Inherited Metabolic Disease

Abstract

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to α-L-iduronidase (IDUA) deficiency that results in the accumulation of glycosaminoglycans (GAG). Systemic gene therapy to MPS I mice can reduce lysosomal storage in the brain, but few data are available regarding the effect upon behavioral function. We investigated the effect of gene therapy with a long-terminal-repeat (LTR)-intact retroviral vector or a self-inactivating (SIN) vector on behavioral function in MPS I mice. The LTR vector was injected intravenously to 6-week-old MPS I mice, and the SIN vector was given to neonatal or 6-week-old mice. Adult-LTR, neonatal-SIN, and adult-SIN-treated mice achieved serum IDUA activity of 235 ± 20 (84-fold normal), 127 ± 10, and 71 ± 7 U/ml, respectively. All groups had reduction in histochemical evidence of lysosomal storage in the brain, with the adult-LTR group showing the best response, while adult-LTR mice had reductions in lysosomal storage in the cristae of the vestibular system. Behavioral evaluation was performed at 8 months. Untreated MPS I mice had a markedly reduced ability to hold onto an inverted screen or climb down a pole. LTR-vector-treated mice had marked improvements on both of these tests, whereas neonatal-SIN mice showed improvement in the pole test. We conclude that both vectors can reduce brain disease in MPS I mice, with the LTR vector achieving higher serum IDUA levels and better correction. Vestibular abnormalities may contribute to mobility problems in patients with MPS I, and gene therapy may reduce symptoms.

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Acknowledgments

We thank Elizabeth Neufeld for sending us the MPS I mice, and Sara Conyers for performing behavioral tests. This work was supported by the Ryan Foundation, the National MPS Society, and the National Institutes of Health (DK66448 awarded to KPP). Histology was supported by P30 DC004665 awarded to R. Chole, and behavioral studies were supported by NIH Neuroscience Blueprint Interdisciplinary Center Core Grant P30 NS057105 awarded to Washington University (DFW). GB received a scholarship from the Conselho Nacional de Desenvolvimento Cientifico (CNPq) of Brazil (200584/2010-3).

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Authors and Affiliations

  1. Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Guilherme Baldo, Yanming Zhang & Katherine P. Ponder

  2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    David F. Wozniak

  3. Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, USA

    Kevin K. Ohlemiller

  4. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA

    Katherine P. Ponder

  5. Gene Therapy Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil

    Guilherme Baldo & Roberto Giugliani

Authors
  1. Guilherme Baldo
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  2. David F. Wozniak
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  3. Kevin K. Ohlemiller
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  4. Yanming Zhang
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  5. Roberto Giugliani
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  6. Katherine P. Ponder
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Correspondence to Katherine P. Ponder.

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Communicated by: Maurizio Scarpa

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Baldo, G., Wozniak, D.F., Ohlemiller, K.K. et al. Retroviral-vector-mediated gene therapy to mucopolysaccharidosis I mice improves sensorimotor impairments and other behavioral deficits. J Inherit Metab Dis 36, 499–512 (2013). https://doi.org/10.1007/s10545-012-9530-x

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  • DOI: https://doi.org/10.1007/s10545-012-9530-x

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