Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial L. Mazzini a, ⁎, I. Ferrero b,c , V. Luparello d , D. Rustichelli b , M. Gunetti b , K. Mareschi b,c , L. Testa a , A. Stecco e , R. Tarletti a , M. Miglioretti f , E. Fava a , N. Nasuelli a , C. Cisari. g , M. Massara g , R. Vercelli h , G.D. Oggioni a , A. Carriero e , R. Cantello a , F. Monaco a , F. Fagioli b a Department of Neurology “Eastern Piedmont” University, “Maggiore della Carità” Hospital, Novara, Italy b Stem Cell Transplantation and Cellular Therapy Unit; Pediatric Onco-Hematology Division, “Regina Margherita” Children's Hospital, Torino, Italy c Department of Pediatrics University of Torino, Torino, Italy d Department of Neurosurgery “San Giovanni Bosco” Hospital, Torino, Italy e Department of Diagnostic and Interventional Radiology, “Eastern Piedmont” University, “Maggiore della Carità” Hospital, Novara, Italy f Department of Psychology, University of Milano-Bicocca, Milano, Italy g Department of Physical Therapy, “Maggiore della Carità” Hospital, Novara, Italy h Department of Pneumology, “Maggiore della Carità” Hospital, Novara, Italy abstract article info Article history: Received 11 March 2009 Revised 31 July 2009 Accepted 2 August 2009 Available online xxxx Keywords: ALS Stem cells Transplantation Cellular therapy Motorneuron Amyotrophic Lateral Sclerosis (ALS) is a devastating incurable disease. Stem-cell-based therapies represent a new possible strategy for ALS clinical research. The objectives of this Phase 1 clinical study were to assess the feasibility and toxicity of mesenchymal stem cell transplantation and to test the impact of a cell therapy in ALS patients. The trial was approved and monitored by the National Institute of Health and by the Ethics Committees of all participating Institutions. Autologous MSCs were isolated from bone marrow, expanded in vitro and analyzed according to GMP conditions. Expanded MSCs were suspended in the autologous cerebrospinal fluid (CSF) and directly transplanted into the spinal cord at a high thoracic level with a surgical procedure. Ten ALS patients were enrolled and regularly monitored before and after transplantation by clinical, psychological, neuroradiological and neurophysiological assessments. There was no immediate or delayed transplant-related toxicity. Clinical, laboratory, and radiographic evaluations of the patients showed no serious transplant-related adverse events. Magnetic resonance images (MRI) showed no structural changes (including tumor formation) in either the brain or the spinal cord. However the lack of post mortem material prevents any definitive conclusion about the vitality of the MSCs after transplantation. In conclusion, this study confirms that MSC transplantation into the spinal cord of ALS patients is safe and that MSCs might have a clinical use for future ALS cell based clinical trials. © 2009 Elsevier Inc. All rights reserved. Introduction Amyotrophic lateral sclerosis (ALS) is a devastating incurable disease that targets motor neurons (Rowland and Shneider, 2001). Despite the relative selectivity of motor neuron cell death, animal and tissue culture models of familial ALS suggest that non-neuronal cells contribute significantly to neuronal dysfunction and death (Boillée et al., 2006; Yamanaka et al., 2008). Marked microglial activation, IgG deposits, and lymphocytic infiltration have been demonstrated in the affected areas of tissue from ALS patients (Henkel et al., 2004). A cell- based therapy may have the advantage of exerting multiple thera- peutic effects (Svendsen and Langston, 2004; Lepore et al., 2008; Suzuki and Svendsen, 2008) at various sites and times within the lesion, as the cells respond to a particular pathological microenviron- ment (Liu et al., 2006) by protecting existing motor neurons from ongoing degeneration. Mesenchymal stem cells (MSCs) are multipotent stem cells that are very attractive in view of a possible cell therapy approach in ALS because of their great plasticity (Chen et al., 2008) and their ability to provide the host tissue with growth factors or modulate the host immune system (Garbuzova-Davis et al., 2006). Their protective effects might function in concert with immunosuppressive and anti- inflammatory activities (Uccelli et al., 2007). MSCs promote “by- stander” immunomodulation (Uccelli et al., 2008) as they can release soluble molecules such as cytokines and chemokines and express immuno-relevant receptors such as chemokine receptors and cell- adhesion molecules (CAMs). These can have anti-inflammatory and anti-proliferative effects on microglial cells and astrocytes, resulting in the induction of a neuroprotective microenvironment (Uccelli et al., 2008). Moreover, bone-marrow-derived MSCs are widely used Experimental Neurology xxx (2009) xxx–xxx ⁎ Corresponding author. Department of Neurology, “Maggiore della Carità” Hospital”, Corso Mazzini 18, 28100 Novara, Italy. Fax: +39 0321 3733298. E-mail address: mazzini.l@libero.it (L. Mazzini). YEXNR-10300; No. of pages: 9; 4C: 0014-4886/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2009.08.007 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr ARTICLE IN PRESS Please cite this article as: Mazzini, L., et al., Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial, Exp. Neurol. (2009), doi:10.1016/j.expneurol.2009.08.007