Enhancement of Motor Function Recovery after Spinal Cord Injury in Mice by Delivery of Brain-Derived Neurotrophic Factor mRNA

Samuel T Crowley,Yuta Fukushima,Satoshi Uchida,Kazunori Kataoka,Keiji Itaka

doi:10.1016/j.omtn.2019.06.016

Abstract

Spinal cord injury (SCI) is a debilitating condition that can cause impaired motor function or full paralysis. In the days to weeks following the initial mechanical injury to the spinal cord, inflammation and apoptosis can cause additional damage to the injured tissues. This secondary injury impairs recovery. Brain-derived neurotrophic factor is a secreted protein that has been shown to improve a variety of neurological conditions, including SCI, by promoting neuron survival and synaptic plasticity. This study treated a mouse model of contusion SCI using a single dose of brain-derived neurotrophic factor (BDNF) mRNA nanomicelles prepared with polyethylene glycol polyamino acid block copolymer directly injected into the injured tissue. BDNF levels in the injured spinal cord tissue were approximately doubled by mRNA treatment. Motor function was monitored using the Basso Mouse Scale and Noldus CatWalk Automated Gait Analysis System for 6 weeks post-injury. BDNF-treated mice showed improved motor function recovery, demonstrating the feasibility of mRNA delivery to treat SCI.

Highlights

Spinal cord injury (SCI) affects approximately 300,000 people per year worldwide
Protein Expression after mRNA Nanomicelle Injection All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion
Expression in injured tissue was measured using a homogenized tissue assay at 48 h post-injection (Figure 1B). mRNA nanomicelles were compared to naked mRNA and to DNA nanomicelles

Summary

Introduction

Spinal cord injury (SCI) affects approximately 300,000 people per year worldwide. Young men make up the majority of cases, usually caused by automobile accidents, falls, sports injuries, and violence.[1,2] The physical and financial effects of SCI are severe, with lifetime healthcare and indirect costs typically reaching into millions of dollars per patient.[3]Recovery from SCI is made difficult by the physiological changes and loss of neurons following the initial injury. Spinal cord injury (SCI) affects approximately 300,000 people per year worldwide. Young men make up the majority of cases, usually caused by automobile accidents, falls, sports injuries, and violence.[1,2] The physical and financial effects of SCI are severe, with lifetime healthcare and indirect costs typically reaching into millions of dollars per patient.[3]. Recovery from SCI is made difficult by the physiological changes and loss of neurons following the initial injury. In the days to weeks following SCI, the injured tissue suffers from inflammation and apoptosis, loss of myelin, and formation of a glial scar that prevents new axon growth. This secondary injury impairs motor function recovery. Methods to prevent the secondary injury might improve long-term recovery by keeping the neural tissue alive during this critical period.[4]

Methods

Results

Conclusion