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Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF

Gene Therapy volume 19, pages 483–493 (2012)Cite this article

A Corrigendum to this article was published on 10 November 2011

Abstract

Intraventricular ependymal infection by adenoviruses expressing brain-derived neurotrophic factor (BDNF) and noggin is sufficient to induce the heterotopic recruitment of new medium spiny neurons to the adult neostriatum, from endogenous subependymal neural progenitor cells. This approach was found to slow disease progression and extend survival in an R6/2 mouse model of Huntington's disease (HD). However, the practical therapeutic value of this strategy is limited by the transient expression and immunogenicity of adenoviral vectors. In addition, it has been unclear whether sustained overexpression of BDNF and noggin would yield similarly sustained neuronal production and striatal recruitment, or whether progenitor depletion or tachyphylaxis might supervene to limit the therapeutic potential of this approach. To address these issues, we used adeno-associated virus serotype 4 (AAV4), an ependymotrophic vector that is neither immunogenic nor neurotoxic, to achieve sustained BDNF and noggin expression. Using AAV4, we found that BDNF and noggin achieved levels sufficient to initiate and maintain, for at least 4 months, ongoing neuronal addition to the neostriatum and olfactory bulb. Over this period, we noted no diminution of treatment-associated neuronal recruitment from resident progenitors. AAV4:BDNF and noggin-induced neuronal addition may thus provide a means to provide longlasting and persistent striatal neuronal replacement in conditions of striatal neuronal loss, such as HD.

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Abbreviations

AAV4:

adeno-associated virus serotype 4

BDNF:

brain-derived neurotrophic factor

IRES:

internal ribosome entry site

DARPP-32:

dopamine- and cyclic-AMP-regulated phosphoprotein of molecular weight 32 000 Da

EGFP:

enhanced green fluorescent protein

BrdU:

5-bromo-2′-deoxyuridine

DCX:

doublecortin

MSN:

medium spiny neuron

OB:

olfactory bulb

CNS:

central nervous system

FMS:

fluorescent microsphere

TUNEL:

terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling

ANOVA:

analysis of variance.

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Acknowledgements

Supported by NINDS R01NS53546 and R37/R01NS29813. We thank Eric Robbins and Michael Toner for technical support, and the Gene Therapy Core Facility of the University of Iowa for producing the AAV2/4-based viruses.

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Authors and Affiliations

  1. Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA

    A Benraiss, E Bruel-Jungerman, G Lu & S A Goldman

  2. Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA

    A Benraiss, E Bruel-Jungerman, G Lu & S A Goldman

  3. Regeneron Pharmaceuticals, Tarrytown, NY, USA

    A N Economides

  4. Department of Medicine, University of Iowa, Iowa City, IA, USA

    B Davidson

  5. Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA

    S A Goldman

  6. These authors contributed equally to this paper.,

    A Benraiss & E Bruel-Jungerman

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  1. A Benraiss
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Correspondence to A Benraiss or S A Goldman.

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Benraiss, A., Bruel-Jungerman, E., Lu, G. et al. Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF. Gene Ther 19, 483–493 (2012). https://doi.org/10.1038/gt.2011.114

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