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Clinical and Translational Medicine
Published in: Clinical and Translational Medicine 1/2014

Open Access 01-12-2014 | Research

Safety of repeated transplantations of neurotrophic factors-secreting human mesenchymal stromal stem cells

Authors: Yael Gothelf, Natalie Abramov, Adrian Harel, Daniel Offen

Published in: Clinical and Translational Medicine | Issue 1/2014

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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.
Appendix
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Literature
1.
Sadan O, Melamed E, Offen D: Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases. Expert Opin Biol Ther 2009, 9: 1487–1497.CrossRefPubMed
2.
Sadan O, Bahat-Stromza M, Barhum Y, Levy YS, Pisnevsky A, Peretz H, Ilan AB, Bulvik S, Shemesh N, Krepel D, Cohen Y, Melamed E, Offen D: Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease. Stem Cells Dev 2009, 18: 1179–1190.CrossRefPubMed
3.
Sadan O, Melamed E, Offen D: Intrastriatal transplantation of neurotrophic factor-secreting human mesenchymal stem cells improves motor function and extends survival in R6/2 transgenic mouse model for Huntington’s disease. PLoS Curr 2012, 4: e4f7f6dc013d4e.PubMedCentralCrossRefPubMed
4.
Sadan O, Shemesh N, Barzilay R, Dadon-Nahum M, Blumenfeld-Katzir T, Assaf Y, Yeshurun M, Djaldetti R, Cohen Y, Melamed E, Offen D: Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease. Exp Neurol 2012, 234: 417–427.CrossRefPubMed
5.
Dadon-Nachum M, Sadan O, Srugo I, Melamed E, Offen D: Differentiated mesenchymal stem cells for sciatic nerve injury. Stem Cell Rev 2011, 7: 664–671.CrossRefPubMed
6.
Li W, Brakefield D, Pan Y, Hunter D, Myckatyn TM, Parsadanian A: Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS. Exp Neurol 2007, 203: 457–471.CrossRefPubMed
7.
Suzuki M, McHugh J, Tork C, Shelley B, Hayes A, Bellantuono I, Aebischer P, Svendsen CN: Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS. Mol Ther 2008, 16: 2002–2010.PubMedCentralCrossRefPubMed
8.
Krakora D, Mulcrone P, Meyer M, Lewis C, Bernau K, Gowing G, Zimprich C, Aebischer P, Svendsen CN, Suzuki M: Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model. Mol Ther 2013, 21: 1602–1610.PubMedCentralCrossRefPubMed
9.
Acsadi G, Anguelov RA, Yang H, Toth G, Thomas R, Jani A, Wang Y, Ianakova E, Mohammad S, Lewis RA, Shy ME: Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum Gene Ther 2002, 13: 1047–1059.CrossRefPubMed
10.
Mohajeri MH, Figlewicz DA, Bohn MC: Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis. Hum Gene Ther 1999, 10: 1853–1866.CrossRefPubMed
11.
Zhao CP, Zhang C, Zhou SN, Xie YM, Wang YH, Huang H, Shang YC, Li WY, Zhou C, Yu MJ, Feng SW: Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy 2007, 9: 414–426.CrossRefPubMed
12.
Edalatmanesh MA, Bahrami AR, Hosseini E, Hosseini M, Khatamsaz S: Neuroprotective effects of mesenchymal stem cell transplantation in animal model of cerebellar degeneration. Neurol Res 2011, 33: 913–920.CrossRefPubMed
13.
von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, Uzunel M, Ringden O, Le Blanc : Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 2012, 30: 1575–1578.CrossRefPubMed
14.
Karussis D, Petrou P, Offen D, Kassis I, Vaknin-Dembinsky A, Argov Z, et al.: Interim analysis of 12 patients with amyotrophic lateral sclerosis (ALS) treated with autologous differentiated mesenchymal stem cells: a phase I/II clinical trial. San Diego: In Proceedings of the 65th Annual Meeting of AAN; 2013.
15.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8: 315–317.CrossRefPubMed
16.
Li L, Wu Y, Wang Y, Wu J, Song L, Xian W, Yuan S, Pei L, Shang Y: Resolvin D1 promotes the interleukin-4-induced alternative activation in BV-2 microglial cells. J Neuroinflammation 2014, 11: 72.PubMedCentralCrossRefPubMed
17.
Murray PJ: The primary mechanism of the IL-10-regulated anti-inflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A 2005, 102: 8686–8691.PubMedCentralCrossRefPubMed
18.
Dadon-Nachum M, Melamed E, Offen D: The “dying-back” phenomenon of motor neurons in ALS. J Mol Neurosci 2011, 43: 470–477.CrossRefPubMed
19.
Liang J, Gu F, Wang H, Hua B, Hou Y, Shi S, Lu L, Sun L: Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE. Nat Rev Rheumatol 2010, 6: 486–489.CrossRefPubMed
20.
Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, Xu Z, Le A, Shi S: Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009, 27: 1421–1432.PubMedCentralCrossRefPubMed
21.
Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, Hua B, Liu B, Ye S, Hu X, Xu W, Zeng X, Hou Y, Gilkeson GS, Silver RM, Lu L, Shi S: Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 2010, 62: 2467–2475.CrossRefPubMed
22.
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, Bulte JW, Petrou P, Ben-Hur T, Abramsky O, Slavin S: Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010, 67: 1187–1194.PubMedCentralCrossRefPubMed
23.
Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, Testa L, Stecco A, Tarletti R, Miglioretti M, Fava E, Nasuelli N, Cisari C, Massara M, Vercelli R, Oggioni GD, Carriero A, Cantello R, Monaco F, Fagioli F: Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial. Exp Neurol 2010, 223: 229–237.CrossRefPubMed
24.
Mazzini L, Mareschi K, Ferrero I, Miglioretti M, Stecco A, Servo S, Carriero A, Monaco F, Fagioli F: Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy 2012, 14: 56–60.CrossRefPubMed
25.
Alegre ML, Florquin S, Goldman M: Cellular mechanisms underlying acute graft rejection: time for reassessment. Curr Opin Immunol 2007, 19: 563–568.CrossRefPubMed
26.
Wang Y, Han ZB, Ma J, Zuo C, Geng J, Gong W, Sun Y, Li H, Wang B, Zhang L, He Y, Han ZC: A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys. Stem Cells Dev 2012, 21: 1401–1408.CrossRefPubMed
27.
Petrou P, Argov A, Lennon VA, Gotkine M, Kassis I, Vaknin-Dembinsky A, Ben-Hur T, Offen D, Abramsky O, Melamed E, Karussis D: Rare combination of myasthenia and motor neuronopathy, responsive to MSC-NTF stem cell therapy. Muscle Nerve 2014, 49: 455–457.CrossRefPubMed
Metadata
Title
Safety of repeated transplantations of neurotrophic factors-secreting human mesenchymal stromal stem cells
Authors
Yael Gothelf
Natalie Abramov
Adrian Harel
Daniel Offen
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2014
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/2001-1326-3-21

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