title: Safety of repeated transplantations of neurotrophic factors-secreting human mesenchymal stromal stem cells.
abstract: BACKGROUND
  Therapies based on mesenchymal stem cells (MSC) have been shown to have potential benefit in several clinical studies. We have shown that, using a medium-based approach, MSC can be induced to secrete elevated levels of neurotropic factors, which have been shown to have protective effects in animal models of neurodegenerative diseases. These cells, designated MSC-NTF cells (Neurotrophic factor-secreting MSC, also known as NurOwn™) derived from the patient's own bone marrow, have been recently used for Phase I/II and Phase IIa clinical studies in patients with Amyotrophic Lateral Sclerosis (ALS). In these studies, ALS patients were subjected to a single administration of autologous MSC-NTF cells. The data from these studies indicate that the single administration of MSC-NTF cells is safe and well tolerated. In a recently published case report, it was shown that repeated MSC-NTF injections in an ALS patient treated on a compassionate basis were safe and well tolerated [Muscle Nerve 49:455-457, 2014].
  
  
  METHODS
  In the current study we studied the toxicity and tolerability of three consecutive intramuscular injections (IM) of cryopreserved human MSC-NTF cells in C57BL/B6 mice to investigate the effect of repeated administration of these cells.
  
  
  RESULTS
  Monitoring of clinical signs and immune reactions showed that repeated injections of the cells did not lead to any serious adverse events. Pathology, histology and blood biochemistry parameters tested were found to be within normal ranges with no sign of tumor formation.
  
  
  CONCLUSIONS
  Based on these results we conclude that repeated injections of human MSC-NTF are well tolerated in mice. The results of this study suggest that if the outcomes of additional clinical studies point to the need for repeated treatments, such option can be considered safe.
authors.affiliation: BrainStorm Cell Therapeutics, POB 10019, Kiryat Aryeh, Petach Tikva 49001, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Gothelf
authors.affiliation: BrainStorm Cell Therapeutics, POB 10019, Kiryat Aryeh, Petach Tikva 49001, Israel.
authors.forename: Natalie
authors.initials: N
authors.lastname: Abramov
authors.affiliation: BrainStorm Cell Therapeutics, POB 10019, Kiryat Aryeh, Petach Tikva 49001, Israel.
authors.forename: Adrian
authors.initials: A
authors.lastname: Harel
authors.affiliation: BrainStorm Cell Therapeutics, POB 10019, Kiryat Aryeh, Petach Tikva 49001, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
keywords: ALS; Cryopreservation; Mesenchymal stromal cells; Repeat injections; Stem cells
references.citation: Stem Cells. 2012 Jul;30(7):1575-8
references.pmid: 22553154
references.citation: Expert Opin Biol Ther. 2009 Dec;9(12):1487-97
references.pmid: 19821796
references.citation: Mol Ther. 2008 Dec;16(12):2002-10
references.pmid: 18797452
references.citation: Mol Ther. 2013 Aug;21(8):1602-10
references.pmid: 23712039
references.citation: Stem Cells Dev. 2009 Oct;18(8):1179-90
references.pmid: 19243240
references.citation: PLoS Curr. 2012 Jul 10;4:e4f7f6dc013d4e
references.pmid: 22953237
references.citation: Cytotherapy. 2006;8(4):315-7
references.pmid: 16923606
references.citation: Cytotherapy. 2012 Jan;14(1):56-60
references.pmid: 21954839
references.citation: Stem Cell Rev Rep. 2011 Sep;7(3):664-71
references.pmid: 21327572
references.citation: J Neuroinflammation. 2014 Apr 05;11:72
references.pmid: 24708771
references.citation: Nat Rev Rheumatol. 2010 Aug;6(8):486-9
references.pmid: 20517294
references.citation: Stem Cells Dev. 2012 Jun 10;21(9):1401-8
references.pmid: 21958114
references.citation: Hum Gene Ther. 1999 Jul 20;10(11):1853-66
references.pmid: 10446925
references.citation: Exp Neurol. 2010 May;223(1):229-37
references.pmid: 19682989
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8686-91
references.pmid: 15937121
references.citation: Muscle Nerve. 2014 Mar;49(3):455-7
references.pmid: 24327321
references.citation: Hum Gene Ther. 2002 Jun 10;13(9):1047-59
references.pmid: 12067438
references.citation: Exp Neurol. 2007 Feb;203(2):457-71
references.pmid: 17034790
references.citation: Neurol Res. 2011 Nov;33(9):913-20
references.pmid: 22080991
references.citation: Exp Neurol. 2012 Apr;234(2):417-27
references.pmid: 22285250
references.citation: Arch Neurol. 2010 Oct;67(10):1187-94
references.pmid: 20937945
references.citation: Stem Cells. 2009 Jun;27(6):1421-32
references.pmid: 19489103
references.citation: Curr Opin Immunol. 2007 Oct;19(5):563-8
references.pmid: 17720467
references.citation: Arthritis Rheum. 2010 Aug;62(8):2467-75
references.pmid: 20506343
references.citation: J Mol Neurosci. 2011 Mar;43(3):470-7
references.pmid: 21057983
references.citation: Cytotherapy. 2007;9(5):414-26
references.pmid: 17786603