591 Therapeutic Delivery (2014) 5(5), 591–607 ISSN 2041-5990 Therapeutic Delivery Review part of 10.4155/TDE.14.20 © 2014 Future Science Ltd Spinal cord injury is a complex pathology often resulting in functional impairment and paralysis. Gene therapy has emerged as a possible solution to the problems of limited neural tissue regeneration through the administration of factors promoting axonal growth, while also offering long-term local delivery of therapeutic molecules at the injury site. Of note, gene therapy is our response to the requirements of neural and glial cells following spinal cord injury, providing, in a time-dependent manner, growth substances for axonal regeneration and eliminating axonal growth inhibitors. Herein, we explore different gene therapy strategies, including targeting gene expression to modulate the presence of neurotrophic growth or survival factors and increase neural tissue plasticity. Special attention is given to describing advances in viral and non- viral gene delivery systems, as well as the available routes of gene delivery. Finally, we discuss the future of combinatorial gene therapies and give consideration to the implementation of gene therapy in humans. Spinal cord injury (SCI) is a complex multi- staged process leading to an increase of the initial injury site and persistent functional disability. A number of factors contribute to the nonpermissive microenvironment at the injury site that are responsible, at least in part, for the failure in neuroregeneration and the lack of recovery after SCI: these factors include inflammatory mediators that increase neuroglial cell death, a lack of neurotrophic support, and the formation of cysts and glial scarring tissue [1–3] . Reports from human clinical trials and the lack of a standardized therapeutic approach for treatment of SCI reveal the necessity of new therapies, not only focused on the injury as a single entity, but on the neural cells involved and their microenvironment, preventing neural tissue loss and glial scar formation, as well as improving neural regeneration and axonal growth after injury [4] . Gene therapy has emerged as a prom- ising therapeutic approach capable of addressing these deficiencies from within the injured neural tissues, modifying the SCI microenvironment and promoting regenerative response of injured neurons through the supplemental delivery of pro- teins necessary for axonal growth [5,6] . Thera- peutic strategies are also focused on the res- toration of the intrinsic regenerative state of the injured neurons, as well as the specific removal or blockade of growth inhibitory molecules [7,8] . Several studies have reported the direct administration of intrathecal or intraspinal growth factors to enhance axo- nal sprouting, the application of guidance proteins to lead axonal regeneration, as well as the elimination of specific noxious factors surrounding these injured axons, including chondroitin sulphate proteoglycans (CSPGs) and myelin proteins (i.e., Nogo and myelin associated glycoprotein [MAG]) [9–11] . As an example, chondroitinase ABC (ChABC) has been used as a specific agent to degrade CSPGs in order to remove glial scar and extracellular matrix, both inhibitors of axonal growth [12] . A degree of success in promot- ing axonal growth has been achieved when applying these non-gene therapy treatments in animal models, but multiple deficiencies have been identified, including that the Gene therapy strategies for the treatment of spinal cord injury Kenzo Uchida* ,1 , Hideaki Nakajima 1 , Alexander Rodriguez Guerrero 1 , William EB Johnson 2 , Wagih El Masri 3 & Hisatoshi Baba 1 1 Department of Orthopaedics & Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23, Eiheiji, Fukui 910–1193, Japan 2 Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK 3 Midlands Centre for Spinal Injuries: Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, Shropshire, SY10 7AG, UK *Author for correspondence: Tel.: +81 776 61 8383 Fax: +81 776 61 8125 kuchida@u-fukui.ac.jp For reprint orders, please contact reprints@future-science.com