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      Intraspinal Neural Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: Phase 1 Trial Outcomes

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          Abstract

          Objective

          The US Food and Drug Administration–approved trial, “A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,” is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects.

          Methods

          Preliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures.

          Results

          The cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials.

          Interpretation

          This is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.

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          Most cited references19

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          Single factors direct the differentiation of stem cells from the fetal and adult central nervous system.

          Identifying the signals that regulate stem cell differentiation is fundamental to understanding cellular diversity in the brain. In this paper we identify factors that act in an instructive fashion to direct the differentiation of multipotential stem cells derived from the embryonic central nervous system (CNS). CNS stem cell clones differentiate to multiple fates: neurons, astrocytes, and oligodendrocytes. The differentiation of cells in a clone is influenced by extracellular signals: Platelet-derived growth factor (PDGF-AA, -AB, and -BB) supports neuronal differentiation. In contrast, ciliary neurotrophic factor and thyroid hormone T3 act instructively on stem cells to generate clones of astrocytes and oligodendrocytes, respectively. Adult stem cells had remarkably similar responses to these growth factors. These results support a simple model in which transient exposure to extrinsic factors acting through known pathways initiates fate decisions by multipotential CNS stem cells.
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            Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients.

            Advances in stem cell biology have generated intense interest in the prospect of transplanting stem cells into the nervous system for the treatment of neurodegenerative diseases. Here, we report the results of an ongoing phase I trial of intraspinal injections of fetal-derived neural stems cells in patients with amyotrophic lateral sclerosis (ALS). This is a first-in-human clinical trial with the goal of assessing the safety and tolerability of the surgical procedure, the introduction of stem cells into the spinal cord, and the use of immunosuppressant drugs in this patient population. Twelve patients received either five unilateral or five bilateral (10 total) injections into the lumbar spinal cord at a dose of 100,000 cells per injection. All patients tolerated the treatment without any long-term complications related to either the surgical procedure or the implantation of stem cells. Clinical assessments ranging from 6 to 18 months after transplantation demonstrated no evidence of acceleration of disease progression due to the intervention. One patient has shown improvement in his clinical status, although these data must be interpreted with caution since this trial was neither designed nor powered to measure treatment efficacy. These results allow us to report success in achieving the phase I goal of demonstrating safety of this therapeutic approach. Based on these positive results, we can now advance this trial by testing intraspinal injections into the cervical spinal cord, with the goal of protecting motor neuron pools affecting respiratory function, which may prolong life for patients with ALS. Copyright © 2012 AlphaMed Press.
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              Stem cell technology for neurodegenerative diseases.

              Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases. Copyright © 2011 American Neurological Association.
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                Author and article information

                Journal
                Ann Neurol
                Ann. Neurol
                ana
                Annals of Neurology
                BlackWell Publishing Ltd (Oxford, UK )
                0364-5134
                1531-8249
                March 2014
                07 March 2014
                : 75
                : 3
                : 363-373
                Affiliations
                [1 ]Department of Neurology, University of Michigan Ann Arbor, MI
                [2 ]Department of Neurosurgery, Emory University School of Medicine Atlanta, GA
                [3 ]Neuralstem Rockville, MD
                [4 ]Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA
                [5 ]Department of Neurology, Emory University School of Medicine Atlanta, GA
                [6 ]A. Alfred Taubman Medical Research Institute, University of Michigan Ann Arbor, MI
                Author notes
                Address correspondence to Dr Feldman, University of Michigan, 109 Zina Pitcher Place, 5017 AAT-BSRB, Ann Arbor, MI 48109. E-mail: efeldman@ 123456umich.edu
                Article
                10.1002/ana.24113
                4005820
                24510776
                ebeea9f3-5a93-4fa6-bd30-a343f2b07267
                © 2014 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 03 October 2013
                : 17 January 2014
                : 25 January 2014
                Categories
                Research Articles

                Neurology
                Neurology

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