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Efficient central nervous system AAVrh10-mediated intrathecal gene transfer in adult and neonate rats

Gene Therapy volume 22, pages 316–324 (2015)Cite this article

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Abstract

Intracerebral administration of recombinant adeno-associated vector (AAV) has been performed in several clinical trials. However, delivery into the brain requires multiple injections and is not efficient to target the spinal cord, thus limiting its applications. To assess widespread and less invasive strategies, we tested intravenous (IV) or intrathecal (that is, in the cerebrospinal fluid (CSF)) delivery of a rAAVrh10-egfp vector in adult and neonate rats and studied the effect of the age at injection on neurotropism. IV delivery is more efficient in neonates and targets predominantly Purkinje cells of the cerebellum and sensory neurons of the spinal cord and dorsal root ganglia. A single intra-CSF administration of AAVrh10, single strand or oversized self-complementary, is efficient for the targeting of neurons in the cerebral hemispheres, cerebellum, brainstem and spinal cord. Green fluorescent protein (GFP) expression is more widespread in neonates when compared with adults. More than 50% of motor neurons express GFP in the three segments of the spinal cord in neonates and in the cervical and thoracic regions in adults. Neurons are almost exclusively transduced in neonates, whereas neurons, astrocytes and rare oligodendrocytes are targeted in adults. These results expand the possible routes of delivery of AAVrh10, a serotype that has shown efficacy and safety in clinical trials concerning neurodegenerative diseases.

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Acknowledgements

We thank the vector core of the Atlantic Gene Therapies Institute (AGT) in Nantes for the preparation of the rAAV vectors, Oumeya Adjali and Johanne Le Duff for the seroneutralization assay and the Boisbonne Centre for assistance with animal production and care. This work was supported by grants from the Association Française contre les Myopathies (AFM), the National French Academy of Medicine and an additional grant from ‘Investissement d'Avenir—ANR-11-INBS-0011’—NeurATRIS: A Translational Research Infrastructure for Biotherapies in Neurosciences’.

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Authors and Affiliations

  1. INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France

    J Hordeaux, L Dubreil, J Deniaud, F Iacobelli, S Moreau, M Ledevin, Y Cherel & M-A Colle

  2. LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France

    J Hordeaux, L Dubreil, J Deniaud, F Iacobelli, S Moreau, M Ledevin, Y Cherel & M-A Colle

  3. LUNAM Université, Université de Nantes, Nantes, France

    J Hordeaux

  4. INSERM UMR1089, Atlantic Gene Therapies, Nantes, France

    C Le Guiner, V Blouin, J Le Duff, A Mendes-Madeira, F Rolling & P Moullier

  5. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA

    P Moullier

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  1. J Hordeaux
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Correspondence to M-A Colle.

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Hordeaux, J., Dubreil, L., Deniaud, J. et al. Efficient central nervous system AAVrh10-mediated intrathecal gene transfer in adult and neonate rats. Gene Ther 22, 316–324 (2015). https://doi.org/10.1038/gt.2014.121

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