Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury

Kentaro Hayakawa; Satoshi Uchida; Toru Ogata; Sakae Tanaka; Kazunori Kataoka; Keiji Itaka

doi:10.1016/j.jconrel.2014.10.027

Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury

J Control Release. 2015 Jan 10:197:1-9. doi: 10.1016/j.jconrel.2014.10.027. Epub 2014 Nov 4.

Authors

Kentaro Hayakawa¹, Satoshi Uchida², Toru Ogata³, Sakae Tanaka⁴, Kazunori Kataoka⁵, Keiji Itaka⁶

Affiliations

¹ Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for the Persons with Disabilities, Saitama, Japan; Sensory and Motor System Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
² Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for the Persons with Disabilities, Saitama, Japan.
⁴ Sensory and Motor System Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
⁶ Sensory and Motor System Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: itaka-ort@umin.net.

PMID: 25449800
DOI: 10.1016/j.jconrel.2014.10.027

Abstract

Spinal cord injury (SCI) is a serious clinical problem that suddenly deprives patients of neurologic function and drastically diminishes their quality of life. Gene introduction has the potential to be effective for various pathological states of SCI because various proteins can be produced just by modifying nucleic acid sequences. In addition, the sustainable protein expression allows to maintain its concentration at an effective level at the target site in the spinal cord. Here we propose an approach using a polyplex system composed of plasmid DNA (pDNA) and a cationic polymer, poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)], that has high capacity to promote endosome escape and the long-term safety by self-catalytically degrading within a few days. We applied brain-derived neurotrophic factor (BDNF)-expressing pDNA for SCI treatment by intrathecal injection of PAsp(DET)/pDNA polyplex. A single administration of polyplex for experimental SCI provided sufficient therapeutic effects including prevention of neural cell death and enhancement of motor function recovery. This lasted for a few weeks after SCI, demonstrating the capability of this system to express BDNF in a safe and responsible manner for treatment of various pathological states in SCI.

Keywords: Brain-derived neurotrophic factor (BDNF); Gene delivery; Intrathecal injection; Polyplex; Spinal cord injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Behavior, Animal
Brain-Derived Neurotrophic Factor / genetics*
Cytokines / genetics
DNA / administration & dosage*
Female
Gene Transfer Techniques
Injections, Spinal
Mice, Inbred C57BL
Peptides / administration & dosage*
Plasmids
Polymers / administration & dosage*
Spinal Cord Injuries / genetics
Spinal Cord Injuries / physiopathology
Spinal Cord Injuries / therapy*

Substances

Brain-Derived Neurotrophic Factor
Cytokines
PAsp(DET)
Peptides
Polymers
DNA