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BY SAM WU, BS, KEVIN T. FITZGERALD, SJ, PhD, and JAMES GIORDANO, PhD
Central neurotrauma: epidemiological and social impacts
Central neurotrauma – or insult to the central nervous system that results in disturbance or loss of neural circuitry, axonal pathways, or neural cells – such as, spinal cord injury (SCI) traumatic brain injury (TBI), and stroke can incur significant impact on patients’ quality of life (Struzyna, et al., 2017; Wu, FitzGerald, and Giordano, 2018). The National Spinal Cord Injury Statistical Center estimates that in 2017, 285,000 persons in the U.S. were living with spinal cord injury (SCI) (National Spinal Cord Injury Database, 2017). In addition, TBI affects approximately 1.5-2 million persons annually in the U.S., with 75,000 to 100,000 of these cases being severe (Johnson, Stewart, and Smith, 2013; Bose, Hou, and Thompson, 2015), while stroke causes 1 out of every 20 deaths in the US annually (Yang, et al., 2017).
The impact of central neurotrauma can be both short- and long-term, with neurological damage and accompanying symptoms lasting for months, years, or even for the remainder of a person’s life. In part, this is because the adult nervous system has only limited ability to regenerate neurons and repair itself following major injury (Struzyna, et al., 2017; Wu, FitzGerald, and Giordano, 2018). Signs and symptoms vary with the type and severity of neurotrauma, and can include sensory, motor and autonomic impairment (Johnson, Stewart, and Smith, 2013; Bose, Hou, and Thompson, 2015; Tsintou, Dalamagkas, and Seifalian, 2015). While pharmacological and surgical interventions can provide some value in managing certain symptoms, these approaches are often of only limited benefit, and do not repair structural damage or lead to replacement of lost tissue (Kabu, et al., 2016; Diaz-Arrastia, et al., 2014; Bansal, et al., 2014; Cramer, 2015).
The potential of regenerative therapies
In light of this situation, there are considerable clinical and socioeconomic incentives to develop more effective regenerative treatments for central neurotrauma. Among these are cell-based approaches, intended for use either singularly or in combination with pharmacological and/or structural treatments (Fouad, et al., 2005; Oraee-Yazdani, et al., 2016; Bento, et al., 2017). Therapies currently being explored for neuro-regenerative and reparative properties involve the use of pluripotent cells derived from embryonic stem cells, fetal stem cells, mesenchymal stem cells, adult neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), Schwann cells, or olfactory ensheathing cells (Wu, FitzGerald, Giordano, 2018).
Preclinical trials of some of these cell-based therapies have had promising outcomes, and are facilitating the possible use of certain types of stem cell interventions for central neurotrauma in human clinical applications. For example, transplanted NSCs have provided neuroprotection, neurotrophic support, immunomodulation, and cell replacement – all of which enable neuroregeneration in the injured CNS (Martino and Pluchino, 2006; Jin, et al., 2011; Pluchino, et al., 2005; Bonner, et al., 2011). Furthermore, mesenchymal stem cells, which are relatively easy to obtain from multiple allogeneic and autologous sources, have been widely used in SCI clinical trials (Wu, FitzGerald, Giordano, 2018). In contrast, translation of other stem cell-based therapies, such as those involving embryonic stem cells or fetal stem cells, have been hindered by technical and ethical challenges related to procurement, transplantation (Nakamura and Okano, 2013; Hockemeyer and Jaenisch, 2016), and safety (Sadowski, et al, 2010; Webowetski-Ogilvie, et al., 2009).
Reprogramming strategies open the door for new possibilities
Improved techniques for cellular reprogramming have enabled the use of other autologous cell sources to be induced to become pluri- or multi-potent stem cells. These reprogrammed cells can alleviate concerns about incompatibility and rejection when transplanted. Combinations of specific transcription factors can be used to generate iPSCs or NSCs from autologous somatic cells (such as fibroblasts, melanocytes, adipocytes, mesenchymal stem cells, cord blood, and others) (Yamanaka, Ralston, and Stephenson, 2006; Kim, et al., 2009; Sun, et al., 2009). Additionally, reprogramming techniques can be used to convert somatic cells directly into neural precursor cells (NPCs) or NSCs, without having to go through intermediate pluripotent stages that may increase the risk of mutagenesis and tumorigenicity (Kelaini, Cochrane and Margariti, 2014; Lujan, et al., 2012; Shahbazi, et al., 2016; Wu, FitzGerald, Giordano, 2018).
Persistent concerns
While research suggests the potential of these innovative stem cell-based therapies for neuro-regeneration and repair, ongoing technical, ethical, legal, and social issues remain and must be addressed. These issues include the validity of patient informed consent given for a particular procedure (in part due to the relative lack of information about the long-term characteristics of reprogrammed cells), the provision and distribution of stem cell resources (inclusive of possible venues for medical tourism), and the importance – if not necessity – of continuing studies of, and clinical care for, those patients receiving reprogrammed neural stem cells (Giordano, 2011; Giordano, 2017; Giordano, 2015; Wu, FitzGerald, and Giordano, 2018).
With reflection upon the past, engagement in the present, and a keen and prudent eye toward the future, it is likely that the most viable regenerative approach to treating central neurotrauma will involve a combination of customizable interventions, inclusive of the use of current and newly developed stem cell technologies. A priority toward realizing these treatments will be the time- and cost-efficient development of high-quality cells that can be translated into safe, affordable and accessible clinical therapies. To achieve this goal will require the increased and ongoing cooperation and collaboration of science, medicine, economics, and policy to ensure that the most valuable therapies are pursued and provided to patients in need.
See On the Viability and Potential Value of Stem Cells for Repair and Treatment of Central Neurotrauma: Overview and Speculations for a more comprehensive review of current and emerging stem cell technologies for central neurotrauma.
ABOUT THE AUTHORS
Sam Wu, BS is Program Manager and Research Assistant at the Pellegrino Center for Clinical Bioethics. Sam is completing a MS in Clinical and Translational Research at Georgetown University.
Kevin T. FitzGerald, SJ, PhD is the John A. Creighton University Chair and Professor in the Creighton University School of Medicine, Department of Medical Education. He joins Creighton from Georgetown University, where he was the Dr. David Lauler Chair of Catholic Health Care Ethics in the Pellegrino Center for Clinical Bioethics.
James Giordano, PhD, MPhil is Chief of the Neuroethics Studies Program and Scholar-in-Residence at the Pellegrino Center for Clinical Bioethics, Professor in the Departments of Neurology and Biochemistry at Georgetown University Medical Center. He is also Distinguished Visiting Professor of Brain Science, Health Promotions and Ethics at the Coburg University of Applied Sciences, Health Promotions and Ethics at the Coburg University of Applied Sciences, Coburg, Germany. He currently serves as an appointed member of the US Department of Health and Human Services Secretary’s Advisory Council on Human Research Protections.
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