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      Human neural stem cell transplantation in ALS: initial results from a phase I trial

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      Journal of Translational Medicine

      BioMed Central

      Phase I trial, Foetal human neural stem cells, Cell therapy, ALS, Advanced therapies

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          We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board.


          Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials.


          No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease.


          We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.

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          Most cited references 32

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          Stem cells in human neurodegenerative disorders--time for clinical translation?

          Stem cell-based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.
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            Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis.

            Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. We established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis--experimental autoimmune encephalomyelitis (EAE) in the mouse--either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.
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              Neural stem cells and neurospheres--re-evaluating the relationship.

              For most of the past century, the prospect of replacing lost or damaged cells in the central nervous system (CNS) was hampered by the opinion that the adult mammalian CNS was incapable of generating new nerve cells. This belief, like most dogmas, was essentially founded on a lack of experimental evidence to the contrary. The overturning of this 'no new neuron' hypothesis began midway through the twentieth century with a series of reports documenting neurogenesis in the postnatal and adult brain, continued with the isolation and in vitro culture of neurogenic cells from the adult mammalian brain, and culminated in the discovery of a population of multipotent, self-renewing cells in the adult CNS (that is, bona fide neural stem cells). Although a variety of techniques were initially used, the neurosphere assay (NSA) rapidly emerged as the assay of choice and has since become a valuable tool for isolating, and understanding the biology of, embryonic and adult CNS stem cells. Like all technologies, it is not without its limitations. In this article we will highlight several shortcomings of the assay related to its application and interpretation that we believe have led to a significant body of research whose conclusions may well be misleading.

                Author and article information

                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                27 January 2015
                27 January 2015
                : 13
                [ ]Department of Neurology, Eastern Piedmont University, Maggiore della Carità Hospital, Corso Mazzini n. 18-28100, Novara, Italy
                [ ]Laboratorio Cellule Staminali, Cell Factory e Biobanca, Terni Hospital, via Tristano di Joannuccio 1, 05100 Terni, Italy
                [ ]IRCCS Casa Sollievo della Sofferenza, viale dei Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy
                [ ]Biotechnology and Bioscience Department Bicocca University, Piazza della Scienza 2, 20126 Milan, Italy
                [ ]Department of Neuroscience, “Santa Maria” Hospital, Terni via Tristano di Joannuccio 1, 05100 Terni, Italy
                [ ]Department of Physical Therapy, Maggiore della Carità Hospital, Corso Mazzini n. 18-28100, Novara, Italy
                [ ]Department of Diagnostic and Interventional Radiology, “Eastern Piedmont” University, “Maggiore della Carità” Hospital, Corso Mazzini n. 18-28100, Novara, Italy
                [ ]Department of Neuroscience, University of Padova, Via Giustiniani, 2 – 35100, Padova, Italy
                [ ]Department of Neurology Emory University, 201 Dowman Dr, Atlanta, GA 30322 USA
                [ ]Department of Neurosurgery Emory University, 201 Dowman Dr, Atlanta, GA 30322 USA
                [ ]Fondazione Cellule Staminali di Terni, Terni Hospital, via Tristano di Joannuccio 1, 05100 Terni, Italy
                © Mazzini et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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                als, advanced therapies, foetal human neural stem cells, cell therapy, phase i trial


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