title: Efficient central nervous system AAVrh10-mediated intrathecal gene transfer in adult and neonate rats.
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.
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France [3] LUNAM Université, Université de Nantes, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Hordeaux
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: L
authors.initials: L
authors.lastname: Dubreil
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Deniaud
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: F
authors.initials: F
authors.lastname: Iacobelli
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Moreau
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Ledevin
authors.affiliation: INSERM UMR1089, Atlantic Gene Therapies, Nantes, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Guiner
authors.affiliation: INSERM UMR1089, Atlantic Gene Therapies, Nantes, France.
authors.forename: V
authors.initials: V
authors.lastname: Blouin
authors.affiliation: INSERM UMR1089, Atlantic Gene Therapies, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Le Duff
authors.affiliation: INSERM UMR1089, Atlantic Gene Therapies, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Mendes-Madeira
authors.affiliation: INSERM UMR1089, Atlantic Gene Therapies, Nantes, France.
authors.forename: F
authors.initials: F
authors.lastname: Rolling
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Cherel
authors.affiliation: 1] INSERM UMR1089, Atlantic Gene Therapies, Nantes, France [2] Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Moullier
authors.affiliation: 1] INRA UMR703, Animal Pathophysiology and Biotherapy for Muscle and Nervous System Diseases, Atlantic Gene Therapies, Nantes, France [2] LUNAM Université, ONIRIS, Nantes-Atlantic National College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors.forename: M-A
authors.initials: MA
authors.lastname: Colle
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000831:Animals, Newborn; D005727:Ganglia, Spinal / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D011689:Purkinje Cells / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*