title: Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates.
abstract: Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus-9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, we evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. We found widespread transgene expression throughout the spinal cord in mice and nonhuman primates when using a 10 times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. We present a detailed analysis of transduction levels throughout the brain, brainstem, and spinal cord of nonhuman primates, providing new guidance for translation toward therapy for a wide range of neurodegenerative disorders.
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Meyer
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Schmelzer
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Braun
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: McGovern
authors.affiliation: 1] The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Shibi
authors.initials: S
authors.lastname: Likhite
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Michels
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Govoni
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Fitzgerald
authors.affiliation: Mannheimer Foundation, Inc., Homestead, Florida, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Morales
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.affiliation: 1] The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA [3] Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.affiliation: Department of Molecular & Cellular Biochemistry, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
authors.affiliation: 1] The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA [3] Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kaspar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007268:Injections, Epidural; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D018076:DNA, Complementary; D055533:Survival of Motor Neuron 1 Protein