Short Communication

Gene Therapy (2017) 24, 325–332; doi:10.1038/gt.2017.18; published online 20 April 2017

Efficient CNS targeting in adult mice by intrathecal infusion of single-stranded AAV9-GFP for gene therapy of neurological disorders

K Bey1,2,3, C Ciron1,2,3, L Dubreil1,2,3, J Deniaud1,2,3, M Ledevin1,2,3, J Cristini4, V Blouin5, P Aubourg6 and M-A Colle1,2,3

  1. 1INRA/ONIRIS UMR U703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Nantes, France
  2. 2Atlantic Gene Therapies, Nantes, France
  3. 3ONIRIS, CS 40706, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Bretagne Loire University (UBL), Nantes, France
  4. 4Department of Neurosurgery, Nantes Hospital, Nantes, France
  5. 5INSERM UMR 1089, Atlantic Gene Therapies, Nantes, France
  6. 6INSERM U1169, Thérapie Génique, Génétique, Epigénétique en Neurologie, Endocrinologie et Développement de l'Enfant, Université Paris Sud, CEA, Le Kremlin Bicêtre, France

Correspondence: Professor M-A Colle, INRA/ONIRIS UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases; ONIRIS, CS 40706, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, BretagneLoire University (UBL), Nantes 44307, France. E-mail: marie-anne.colle@oniris-nantes.fr

Received 11 November 2016; Revised 17 February 2017; Accepted 28 February 2017
Advance online publication 20 April 2017

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Abstract

Adeno-associated virus (AAV) gene therapy constitutes a powerful tool for the treatment of neurodegenerative diseases. While AAVs are generally administered systemically to newborns in preclinical studies of neurological disorders, in adults the maturity of the blood–brain barrier (BBB) must be considered when selecting the route of administration. Delivery of AAVs into the cerebrospinal fluid (CSF) represents an attractive approach to target the central nervous system (CNS) and bypass the BBB. In this study, we investigated the efficacy of intra-CSF delivery of a single-stranded (ss) AAV9-CAG-GFP vector in adult mice via intracisternal (iCist) or intralumbar (it-Lumb) administration. It-Lumb ssAAV9 delivery resulted in greater diffusion throughout the entire spinal cord and green fluorescent protein (GFP) expression mainly in the cerebellum, cortex and olfactory bulb. By contrast, iCist delivery led to strong GFP expression throughout the entire brain. Comparison of the transduction efficiency of ssAAV9-CAG-GFP versus ssAAV9-SYN1-GFP following it-Lumb administration revealed widespread and specific GFP expression in neurons and motoneurons of the spinal cord and brain when the neuron-specific synapsin 1 (SYN1) promoter was used. Our findings demonstrate that it-Lumb ssAAV9 delivery is a safe and highly efficient means of targeting the CNS in adult mice.