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In utero delivery of rAAV2/9 induces neuronal expression of the transgene in the brain: towards new models of Parkinson’s disease

Abstract

Animal models are essential tools for basic pathophysiological research as well as validation of therapeutic strategies for curing human diseases. However, technical difficulties associated with classical transgenesis approaches in rodent species higher than Mus musculus have prevented this long-awaited development. The availability of viral-mediated gene delivery systems in the past few years has stimulated the production of viruses with unique characteristics. For example, the recombinant adeno-associated virus serotype 9 (rAAV2/9) crosses the blood–brain barrier, is capable of transducing developing cells and neurons after intravenous injection and mediates long-term transduction. Whilst post-natal delivery is technically straightforward, in utero delivery bears the potential of achieving gene transduction in neurons at embryonic stages during which the target area is undergoing development. To test this possibility, we injected rAAV2/9 carrying either A53T mutant human α-synuclein or green fluorescent protein, intracerebroventricularly in rats at embryonic day 16.5. We observed neuronal transgene expression in most regions of the brain at 1 and 3 months after birth. This proof-of-concept experiment introduces a new opportunity to model brain diseases in rats.

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Acknowledgements

MB was the recipient of a MESR fellowship and the France Parkinson Foundation. Slide scanning was performed at the Bordeaux Imaging Center a service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging. Accommodations and experiments were performed in the Service des Animaleries of the University of Bordeaux, supported by the Région Aquitaine. This work was supported by the LABEX BRAIN. The help of Romain Desgranges for Figure 1, as well as Florian Roguet and Laetitia Medan for animal care is acknowledged. We also thank A. Crossman for valuable comments on the manuscript.

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Correspondence to B Dehay.

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EB is Chief Scientific Officer of Motac neuroscience Ltd. The remaining authors declare no conflict of interest.

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Chansel-Debordeaux, L., Bourdenx, M., Dovero, S. et al. In utero delivery of rAAV2/9 induces neuronal expression of the transgene in the brain: towards new models of Parkinson’s disease. Gene Ther 24, 801–809 (2017). https://doi.org/10.1038/gt.2017.84

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