The HIV Tat protein transduction domain improves the biodistribution of β-glucuronidase expressed from recombinant viral vectors (original) (raw)

Nature Biotechnology volume 19, pages 640–644 (2001)Cite this article

Abstract

Treatment of inherited genetic diseases of the brain remains an intractable problem. Methods to improve the distribution of enzymes that are injected or expressed from transduced cells will be required for many human brain therapies. Recent studies showed that a peptide, the protein transduction domain (PTD) from HIV Tat, could improve the distribution of cytoplasmic reporter proteins when administered systemically as fusion proteins or cross-linked chimeras. The utility of this motif for noncytoplasmic proteins has not been determined. Here, we tested how the Tat motif affected uptake and biodistribution of the lysosomal enzyme β-glucuronidase, the protein deficient in the disease mucopolysaccharidosis VII, when expressed from viral vectors. The Tat motif allowed for mannose-6-phosphate (M6P) independent uptake in vitro and significantly increased the distribution of β-glucuronidase secreted from transduced cells after intravenous or direct brain injection in mice of recombinant vectors. Thus, enzymes modified to contain protein transduction motifs may represent a general strategy for improving the distribution of secreted proteins following in vivo gene transfer.

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Acknowledgements

We thank Todd Derksen, Christine McLennan, Inês Martins, Christopher van de Wetering, Bridget Zimmerman, Paul Reimann, and Chad Stocker for assistance. This work was supported by the NIH (HD33531, NS34568, and DK54759), the American Heart Association (HX), the State of Iowa Biosciences Initiative (Q.M.), and the Roy J. Carver Trust (B.L.D.).

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Author notes

  1. Haibin Xia and Qinwen Mao: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, 52242, IA, USA
    Haibin Xia, Qinwen Mao & Beverly L. Davidson
  2. Department of Neurology, Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, 52242, IA, USA
    Beverly L. Davidson
  3. Department of Physiology and Biophysics, Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, 52242, IA, USA
    Beverly L. Davidson

Authors

  1. Haibin Xia
  2. Qinwen Mao
  3. Beverly L. Davidson

Corresponding author

Correspondence toBeverly L. Davidson.

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Xia, H., Mao, Q. & Davidson, B. The HIV Tat protein transduction domain improves the biodistribution of β-glucuronidase expressed from recombinant viral vectors.Nat Biotechnol 19, 640–644 (2001). https://doi.org/10.1038/90242

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