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Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.
Bravo-Hernandez, Mariana; Tadokoro, Takahiro; Navarro, Michael R; Platoshyn, Oleksandr; Kobayashi, Yoshiomi; Marsala, Silvia; Miyanohara, Atsushi; Juhas, Stefan; Juhasova, Jana; Skalnikova, Helena; Tomori, Zoltan; Vanicky, Ivo; Studenovska, Hana; Proks, Vladimir; Chen, PeiXi; Govea-Perez, Noe; Ditsworth, Dara; Ciacci, Joseph D; Gao, Shang; Zhu, Wenlian; Ahrens, Eric T; Driscoll, Shawn P; Glenn, Thomas D; McAlonis-Downes, Melissa; Da Cruz, Sandrine; Pfaff, Samuel L; Kaspar, Brian K; Cleveland, Don W; Marsala, Martin.
Affiliation
  • Bravo-Hernandez M; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Tadokoro T; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Navarro MR; Department of Anesthesiology, University of the Ryukyus, Okinawa, Japan.
  • Platoshyn O; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Kobayashi Y; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Marsala S; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Miyanohara A; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Juhas S; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Juhasova J; Vector Core Laboratory, University of California San Diego, La Jolla, CA, USA.
  • Skalnikova H; Institute of Animal Physiology and Genetics, AS CR v.v.i., Libechov, Czech Republic.
  • Tomori Z; Institute of Animal Physiology and Genetics, AS CR v.v.i., Libechov, Czech Republic.
  • Vanicky I; Institute of Animal Physiology and Genetics, AS CR v.v.i., Libechov, Czech Republic.
  • Studenovska H; Dept. of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Kosice, Slovakia.
  • Proks V; Institute of Neurobiology, Slovak Academy of Sciences, Kosice, Slovakia.
  • Chen P; Department of Biomaterials and Bioanalogous System, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • Govea-Perez N; Department of Biomaterials and Bioanalogous System, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • Ditsworth D; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Ciacci JD; Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • Gao S; Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Zhu W; Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Ahrens ET; Department of Neurosurgery, University of California San Diego, La Jolla, CA, USA.
  • Driscoll SP; Department of Radiology, University of California San Diego, La Jolla, CA, USA.
  • Glenn TD; Department of Radiology, University of California San Diego, La Jolla, CA, USA.
  • McAlonis-Downes M; Department of Radiology, University of California San Diego, La Jolla, CA, USA.
  • Da Cruz S; Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • Pfaff SL; Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • Kaspar BK; Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Cleveland DW; Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Marsala M; Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
Nat Med ; 26(1): 118-130, 2020 01.
Article in En | MEDLINE | ID: mdl-31873312
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pia Mater / Spinal Cord / Gene Transfer Techniques / Dependovirus / Gene Silencing / Amyotrophic Lateral Sclerosis / Motor Neurons / Nerve Degeneration Limits: Animals / Female / Humans / Male Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2020 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pia Mater / Spinal Cord / Gene Transfer Techniques / Dependovirus / Gene Silencing / Amyotrophic Lateral Sclerosis / Motor Neurons / Nerve Degeneration Limits: Animals / Female / Humans / Male Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2020 Document type: Article Affiliation country: United States