title: Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.
abstract: Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood-brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Bevan
authors.forename: Sandra
authors.initials: S
authors.lastname: Duque
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.forename: Pablo R
authors.initials: PR
authors.lastname: Morales
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Braun
authors.forename: Leah
authors.initials: L
authors.lastname: Schmelzer
authors.forename: Curtis M
authors.initials: CM
authors.lastname: Chan
authors.forename: Mary
authors.initials: M
authors.lastname: McCrate
authors.forename: Louis G
authors.initials: LG
authors.lastname: Chicoine
authors.forename: Brian D
authors.initials: BD
authors.lastname: Coley
authors.forename: Paul N
authors.initials: PN
authors.lastname: Porensky
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kolb
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007268:Injections, Epidural; D007269:Injections, Intra-Arterial; D008251:Macaca; D008297:Male; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000628:therapy*; D009457:Neuroglia / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics