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Long-term AAV vector gene and protein expression in mouse brain from a small pan-cellular promoter is similar to neural cell promoters

Gene Therapy volume 16, pages 927–932 (2009)Cite this article

Abstract

The neurogenetic, lysosomal enzyme (LSE) deficiency diseases are characterized by storage lesions throughout the brain; therefore, gene transfer needs to provide widespread distribution of the normal enzyme. Adeno-associated virus (AAV) vectors can be effective in the brain despite limited transduction because LSEs are exported to neighboring cells (cross-correction) to reverse the metabolic deficit. The extent of correction is determined by a combination of the total amount of LSE produced by a vector and the spatial distribution of the vector within the brain. Neuron-specific promoters have been used in the brain because AAV predominantly transduces neurons. However, these promoters are large, using up a substantial amount of the limited cloning capacity of AAV vector genomes. A small promoter that is active in all cells, from the LSE β-glucuronidase (GUSB), has been used for long-term expression in AAV vectors in the brain but the natural promoter is expressed at very low levels. The amount of LSE exported from a cell is proportional to the level of transcription, thus more active promoters would export more LSE for cross-correction, but direct comparisons have not been reported. In this study, we show that in long-term experiments (>6 months) the GUSB minimal promoter (hGBp) expresses the hGUSB enzyme in brain at similar levels as the neuron-specific enolase promoter or the promoter from the latency-associated transcript of herpes simplex virus. The hGBp minimal promoter thus may be useful for long-term expression in the central nervous system of large cDNAs, bicitronic transcription units, self-complimentary or other designs with size constraints in the AAV vector system.

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Acknowledgements

We thank A Polesky, E Cabacungan and T Clarke for excellent technical assistance. This work was supported by NIH grants R01-NS038690 (JHW) and R01-NS029390 (NWF). TH and MAP were partially supported by NIH training grant T32-DK007748.

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Author notes

  1. T Husain

    Present address: 4Current address: US Navy Medical Research Center, Silver Spring, MD, USA.,

  2. M A Passini

    Present address: 5Current address: Genzyme Corp., Framingham, MA, USA.,

Authors and Affiliations

  1. WF Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    T Husain, M A Passini, M K Parente, N W Fraser & J H Wolfe

  2. Stokes Institute, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    T Husain, M A Passini, M K Parente & J H Wolfe

  3. Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    N W Fraser

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Correspondence to J H Wolfe.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Husain, T., Passini, M., Parente, M. et al. Long-term AAV vector gene and protein expression in mouse brain from a small pan-cellular promoter is similar to neural cell promoters. Gene Ther 16, 927–932 (2009). https://doi.org/10.1038/gt.2009.52

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