Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats
2014
Bucher, Thomas | Dubreil, Laurence | Colle, Marie-Anne | Maquigneau, M | Deniaud, Johan | Ledevin, Mireille | Moullier, Philippe | Joussemet, Béatrice | Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE) ; Université de Nantes (UN)-Université de Nantes (UN) | Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher) ; École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS) | Department of Molecular Genetics and Microbiology ; University of Central Florida [Orlando] (UCF) | 'Association Francaise contre les Myopathies' (AFM); SMA-Europe; Fondation d'Entreprises pour la Therapie Genique en Pays de la Loire
Systemic and intracerebrospinal fluid delivery of adeno-associated virus serotype 9 (AAV9) has been shown to achieve widespread gene delivery to the central nervous system (CNS). However, after systemic injection, the neurotropism of the vector has been reported to vary according to age at injection, with greater neuronal transduction in newborns and preferential glial cell tropism in adults. This difference has not yet been reported after cerebrospinal fluid (CSF) delivery. The present study analyzed both neuronal and glial cell transduction in the CNS of cats according to age of AAV9 CSF injection. In both newborns and young cats, administration of AAV9-GFP in the cisterna magna resulted in high levels of motor neurons (MNs) transduction from the cervical (84±5%) to the lumbar (99±1%) spinal cord, demonstrating that the remarkable tropism of AAV9 for MNs is not affected by age at CSF delivery. Surprisingly, numerous oligodendrocytes were also transduced in the brain and in the spinal cord white matter of young cats, but not of neonates, indicating that (i) age of CSF delivery influences the tropism of AAV9 for glial cells and (ii) AAV9 intracisternal delivery could be relevant for both the treatment of MN and demyelinating disorders.
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