Original Article

Gene Therapy (2016) 23, 272–282; doi:10.1038/gt.2015.112; published online 21 January 2016

Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex
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J H Jara1, M J Stanford1, Y Zhu2, M Tu1, W W Hauswirth3, M C Bohn4, S H DeVries2 and P H Özdinler1,5,6

  1. 1Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
  2. 2Department of Ophthalmology and Physiology, University of Florida, Gainesville, FL, USA
  3. 3Department of Ophthalmology, University of Florida, Gainesville, FL, USA
  4. 4Neurobiology 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
  5. 5Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL, USA
  6. 6Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, Chicago, IL, USA

Correspondence: Dr PH Özdinler, Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA. E-mail: ozdinler@northwestern.edu

Received 7 April 2015; Revised 1 November 2015; Accepted 21 December 2015
Advance online publication 21 January 2016

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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 hSOD1G93A 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 hSOD1G93A transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases.