Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Avexis Inc Chicago IL USA

Department of Anesthesiology University of the Ryukyus Okinawa Japan

Department of Biomaterials and Bioanalogous System Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic

Department of Neurosurgery University of California San Diego La Jolla CA USA

Department of Radiology University of California San Diego La Jolla CA USA

Dept of Biophysics Institute of Experimental Physics Slovak Academy of Sciences Kosice Slovakia

Gene Expression Laboratory and the Howard Hughes Medical Institute Salk Institute for Biological Studies La Jolla CA USA

Institute of Animal Physiology and Genetics AS CR v v i Liběchov Czech Republic

Institute of Neurobiology Slovak Academy of Sciences Kosice Slovakia

Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA

Neuroregeneration Laboratory Department of Anesthesiology University of California San Diego La Jolla CA USA

Vector Core Laboratory University of California San Diego La Jolla CA USA

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