Lentiviral Interleukin-10 Gene Therapy Preserves Fine Motor Circuitry and Function After a Cervical Spinal Cord Injury i
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ORIGINAL ARTICLE
Lentiviral Interleukin-10 Gene Therapy Preserves Fine Motor Circuitry and Function After a Cervical Spinal Cord Injury in Male and Female Mice Jessica Y. Chen 1,2 & Emily J. Fu 1 & Paras R. Patel 1 & Alexander J. Hostetler 1 & Hasan A. Sawan 1 & Kayla A. Moss 1 & Sarah E. Hocevar 1,2 & Aileen J. Anderson 3 & Cynthia A. Chestek 1,2,4,5 & Lonnie D. Shea 1,2 Accepted: 6 October 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract In mammals, spinal cord injuries often result in muscle paralysis through the apoptosis of lower motor neurons and denervation of neuromuscular junctions. Previous research shows that the inflammatory response to a spinal cord injury can cause additional tissue damage after the initial trauma. To modulate this inflammatory response, we delivered lentiviral anti-inflammatory interleukin-10, via loading onto an implantable biomaterial scaffold, into a left-sided hemisection at the C5 vertebra in mice. We hypothesized that improved behavioral outcomes associated with anti-inflammatory treatment are due to the sparing of fine motor circuit components. We examined behavioral recovery using a ladder beam, tissue sparing using histology, and electromyogram recordings using intraspinal optogenetic stimulation at 2 weeks post-injury. Ladder beam analysis shows interleukin10 treatment results in significant improvement of behavioral recovery at 2 and 12 weeks post-injury when compared to mice treated with a control virus. Histology shows interleukin-10 results in greater numbers of lower motor neurons, axons, and muscle innervation at 2 weeks post-injury. Furthermore, electromyogram recordings suggest that interleukin-10-treated animals have signal-to-noise ratios and peak-to-peak amplitudes more similar to that of uninjured controls than to that of control injured animals at 2 weeks post-injury. These data show that gene therapy using anti-inflammatory interleukin-10 can significantly reduce tissue damage and subsequent motor deficits after a spinal cord injury. Together, these results suggest that early modulation of the injury response can preserve muscle function with long-lasting benefits. Key Words Gene therapy . biomaterial . spinal cord injury . inflammation . neuromuscular junction
Emily J. Fu and Paras R. Patel contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-020-00946-y) contains supplementary material, which is available to authorized users. * Lonnie D. Shea [email protected] 1
Department of Biomedical Engineering, College of Engineering, University of Michigan, 2200 Bonisteel Boulevard, 1119 Carl A Gerstacker Building, Ann Arbor, MI 48109, USA
2
Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA
4
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA
5
Robotics Pr
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