title: Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex.
abstract: Direct gene delivery to the neurons of interest, without affecting other neuron populations in the cerebral cortex, represent a challenge owing to the heterogeneity and cellular complexity of the brain. Genetic modulation of corticospinal motor neurons (CSMN) is required for developing effective and long-term treatment strategies for motor neuron diseases, in which voluntary movement is impaired. Adeno-associated viruses (AAV) have been widely used for neuronal transduction studies owing to long-term and stable gene expression as well as low immunoreactivity in humans. Here we report that AAV2-2 transduces CSMN with high efficiency upon direct cortex injection and that transduction efficiencies are similar during presymptomatic and symptomatic stages in hSOD1(G93A) transgenic amyotrophic lateral sclerosis (ALS) mice. Our findings reveal that choice of promoter improves selectivity as AAV2-2 chicken β-actin promoter injection results in about 70% CSMN transduction, the highest percentage reported to date. CSMN transduction in both wild-type and transgenic ALS mice allows detailed analysis of single axon fibers within the corticospinal tract in both cervical and lumbar spinal cord and reveals circuitry defects, which mainly occur between CSMN and spinal motor neurons in hSOD1(G93A) transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases.
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Jara
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Stanford
authors.affiliation: Department of Ophthalmology and Physiology, University of Florida, Gainesville, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tu
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Neurobiology Program, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago Research Center Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Bohn
authors.affiliation: Department of Ophthalmology and Physiology, University of Florida, Gainesville, FL, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: DeVries
authors.affiliation: Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.|Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL, USA.|Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Özdinler
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D051379:Mice; D009044:Motor Cortex / Q000378:metabolism*; D016472:Motor Neuron Disease / Q000235:genetics* / Q000628:therapy*; D009046:Motor Neurons / Q000378:metabolism; D014161:Transduction, Genetic