Ethical Considerations in Stem Cell Therapy Studies

Document Type : Review Article

Authors

1 Research Assistant, Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Associate Professor, Department of Anatomical Sciences and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Associate Professor, Department of Reproduction and Development, Reproductive Biomedicine Center, Royan Institute for Animal Biotechnology, Isfahan, Iran

4 Professor, Department of Internal Diseases, Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Stem cells are undifferentiated cells that can turn into any number of differentiated and specific cell types. For years, stem cell assisted therapy has been accepted as a standard treatment method for the management of some diseases. Scientists hope that this method can be expanded and used for the treatment of other diseases. One of the main concerns in the field of stem cell therapy research is the safety of these cells. This article assessed the safety of using mesenchymal fibroblasts, keratinocytes, melanocytes and skeletal myoblasts in clinical trials.Methods: A systematic search of reliable electronic databases was performed in order to find all articles related to safety of the mentioned cells. After studying all the articles critically, the preliminary results were reviewed and criticized by experts through Delphi method. Ultimately, the final draft was reviewed and approved by all the members of the Regional Research Ethics Committee.Findings: Overall, 62 articles were retrieved and studied. Conclusion: Since we did not find any reports of serious complications for fibroblast, keratinocyte and melanocyte cells, especially about their in-vivo uncontrolled proliferation, it is possible to give ethical approval for research in these fields (considering all ethical codes and principles). However, according to serious complications reported for skeletal myoblast cells transplantation, giving ethical approval for using this cell type in human research requires strict commitment to precise methods (such as inclusion criteria, patient follow-up methods, and prophylactic treatments). The ethical approval should be issued by the research ethics committee of the corresponding university after accurate reviews. Finally, repeating previous research which has resulted in arrhythmia and tissue injury is unethical and thus not recommended.

Keywords

References

  1. De HJ, Acin F, Lopez-Quintana A, Florez A, Martinez-Aguilar E, Varela C. Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 2009; 24(5): 321-8.
  2. Perin EC, Silva GV. Autologous cell-based therapy for ischemic heart disease: clinical evidence, proposed mechanisms of action, and current limitations. Catheter Cardiovasc Interv 2009; 73(3): 281-8.
  3. Pendyala L, Goodchild T, Gadesam RR, Chen J, Robinson K, Chronos N, et al. Cellular cardiomyoplasty and cardiac regeneration. Curr Cardiol Rev 2008; 4(2): 72-80.
  4. Das KA. Stem cell therapy for critical limb ischaemia — a review. Indian Journal of Surgery 2009; 71(4): 177-81.
  5. Gersh BJ, Simari RD, Behfar A, Terzic CM, Terzic A. Cardiac cell repair therapy: a clinical perspective. Mayo Clin Proc 2009; 84(10): 876-92.
  6. Wert GD, Mummery C. Human embryonic stem cells: research, ethics and policy. Human Reproduction 2003; 18(4): 672-82.
  7. West TB, Alster TS. Autologous human collagen and dermal fibroblasts for soft tissue augmentation. Dermatol Surg 1998; 24(5): 510-2.
  8. Watson D, Keller GS, Lacombe V, Fodor PB, Rawnsley J, Lask GP. Autologous fibroblasts for treatment of facial rhytids and dermal depressions. A pilot study. Arch Facial Plast Surg 1999; 1(3): 165-70.
  9. Berke G, Blumin J, Sebastian J, Keller G, Revazova E. Vocal cord augmentation with cultured autologous fibroblasts. Bull Exp Biol Med 2000; 130(8): 790-2.
  10. Keller G, Sebastian J, Lacombe U, Toft K, Lask G, Revazova E. Safety of injectable autologous human fibroblasts. Bull Exp Biol Med 2000; 130(8): 786-9.
  11. Boss WK, Jr., Usal H, Fodor PB, Chernoff G. Autologous cultured fibroblasts: a protein repair system. Ann Plast Surg 2000; 44(5): 536-42.
  12. Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg 2002; 41(5): 291-9.
  13. Marston WA, Hanft J, Norwood P, Pollak R. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 2003; 26(6): 1701-5.
  14. Weiss RA, Weiss MA, Beasley KL, Munavalli G. Autologous cultured fibroblast injection for facial contour deformities: a prospective, placebo-controlled, Phase III clinical trial. Dermatol Surg 2007; 33(3): 263-8.
  15. Mitterberger M, Marksteiner R, Margreiter E, Pinggera GM, Colleselli D, Frauscher F, et al. Autologous myoblasts and fibroblasts for female stress incontinence: a 1-year follow-up in 123 patients. BJU Int 2007; 100(5): 1081-5.
  16. McGuire MK, Scheyer ET. A randomized, double-blind, placebo-controlled study to determine the safety and efficacy of cultured and expanded autologous fibroblast injections for the treatment of interdental papillary insufficiency associated with the papilla priming procedure. J Periodontol 2007; 78(1): 4-17.
  17. Strasser H, Marksteiner R, Margreiter E, Pinggera GM, Mitterberger M, Frauscher F, et al. Autologous myoblasts and fibroblasts versus collagen for treatment of stress urinary incontinence in women: a randomised controlled trial. Lancet 2007; 369(9580): 2179-86.
  18. Mitterberger M, Marksteiner R, Margreiter E, Pinggera G, Frauscher F, Ulmer H, et al. Myoblast and fibroblast therapy for post-prostatectomy urinary incontinence: 1-year followup of 63 patients. J Urol 2008; 179(1): 226-31.
  19. Han SK, Kim HS, Kim WK. Efficacy and safety of fresh fibroblast allografts in the treatment of diabetic foot ulcers. Dermatol Surg 2009; 35(9): 1342-8.
  20. http://www.fibrocellscience.com/media/2011/2011_06_22.htm.
  21. Langdon J, Williams DM, Navsaria H, Leigh IM. Autologous keratinocyte grafting: a new technique for intra-oral reconstruction. Br Dent J 1991; 171(3-4): 87-90.
  22. Rue LW, III, Cioffi WG, McManus WF, Pruitt BA, Jr. Wound closure and outcome in extensively burned patients treated with cultured autologous keratinocytes. J Trauma 1993; 34(5): 662-7.
  23. Svensjo T, Yao F, Pomahac B, Eriksson E. Autologous keratinocyte suspensions accelerate epidermal wound healing in pigs. J Surg Res 2001; 99(2): 211-21.
  24. Liu JY, Hafner J, Dragieva G, Seifert B, Burg G. Autologous cultured keratinocytes on porcine gelatin microbeads effectively heal chronic venous leg ulcers. Wound Repair Regen 2004; 12(2): 148-56.
  25. Moustafa M, Simpson C, Glover M, Dawson RA, Tesfaye S, Creagh FM, et al. A new autologous keratinocyte dressing treatment for non-healing diabetic neuropathic foot ulcers. Diabet Med 2004; 21(7): 786-9.
  26. Sakurai T, Miyazaki S, Miyata G, Satomi S, Hori Y. Autologous buccal keratinocyte implantation for the prevention of stenosis after EMR of the esophagus. Gastrointest Endosc 2007; 66(1): 167-73.
  27. Hartmann A, Quist J, Hamm H, Brocker EB, Friedl P. Transplantation of autologous keratinocyte suspension in fibrin matrix to chronic venous leg ulcers: improved long-term healing after removal of the fibrin carrier. Dermatol Surg 2008; 34(7): 922-9.
  28. Schurr MJ, Foster KN, Centanni JM, Comer AR, Wicks A, Gibson AL, et al. Phase I/II clinical evaluation of StrataGraft: a consistent, pathogen-free human skin substitute. J Trauma 2009; 66(3): 866-73.
  29. Gauthier Y, Surleve-Bazeille JE. Autologous grafting with noncultured melanocytes: a simplified method for treatment of depigmented lesions. J Am Acad Dermatol 1992; 26(2 Pt 1): 191-4.
  30. Olsson MJ, Juhlin L. Repigmentation of vitiligo by transplantation of cultured autologous melanocytes. Acta Derm Venereol 1993; 73(1): 49-51.
  31. Olsson MJ, Juhlin L. Transplantation of melanocytes in vitiligo. Br J Dermatol 1995; 132(4): 587-91.
  32. Njoo MD, Westerhof W, Bos JD, Bossuyt PM. A systematic review of autologous transplantation methods in vitiligo. Arch Dermatol 1998; 134(12): 1543-9.
  33. Chen YF, Chang JS, Yang PY, Hung CM, Huang MH, Hu DN. Transplant of cultured autologous pure melanocytes after laser-abrasion for the treatment of segmental vitiligo. J Dermatol 2000; 27(7): 434-9.
  34. Olsson MJ, Juhlin L. Long-term follow-up of leucoderma patients treated with transplants of autologous cultured melanocytes, ultrathin epidermal sheets and basal cell layer suspension. Br J Dermatol 2002; 147(5): 893-904.
  35. Mulekar SV. Melanocyte-keratinocyte cell transplantation for stable vitiligo. Int J Dermatol 2003; 42(2): 132-6.
  36. Mulekar SV. Long-term follow-up study of segmental and focal vitiligo treated by autologous, noncultured melanocyte-keratinocyte cell transplantation. Arch Dermatol 2004; 140(10): 1211-5.
  37. Chen YF, Yang PY, Hu DN, Kuo FS, Hung CS, Hung CM. Treatment of vitiligo by transplantation of cultured pure melanocyte suspension: analysis of 120 cases. J Am Acad Dermatol 2004; 51(1): 68-74.
  38. Mulekar SV. Long-term follow-up study of 142 patients with vitiligo vulgaris treated by autologous, non-cultured melanocyte-keratinocyte cell transplantation. Int J Dermatol 2005; 44(10): 841-5.
  39. Pandya V, Parmar KS, Shah BJ, Bilimoria FE. A study of autologous melanocyte transfer in treatment of stable vitiligo. Indian J Dermatol Venereol Leprol 2005; 71(6): 393-7.
  40. Mulekar SV, Al IA, Al EA, Asaad M. Genital vitiligo treated by autologous, noncultured melanocyte-keratinocyte cell transplantation. Dermatol Surg 2005; 31(12): 1737-9.
  41. Gupta S, Goel A, Kanwar AJ, Kumar B. Autologous melanocyte transfer via epidermal grafts for lip vitiligo. Int J Dermatol 2006; 45(6): 747-50.
  42. Rastogi S, Goyal P, Mangla K, Bhavsar N, Patel H, Rawal RC. Study of transplantation of melanocyte keratinocyte suspension in treatment of vitiligo. Indian Journal of Dermatology 2006; 51(2): 142-4.
  43. Tegta GR, Parsad D, Majumdar S, Kumar B. Efficacy of autologous transplantation of noncultured epidermal suspension in two different dilutions in the treatment of vitiligo. Int J Dermatol 2006; 45(2): 106-10.
  44. Falabella R, Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res 2009; 22(1): 42-65.
  45. Khodadadi L, Shafieyan S, Sotoudeh M, Dizaj AV, Shahverdi A, Aghdami N, et al. Intraepidermal injection of dissociated epidermal cell suspension improves vitiligo. Arch Dermatol Res 2010; 302(8): 593-9.
  46. Herreros J, Prosper F, Perez A, Gavira JJ, Garcia-Velloso MJ, Barba J, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J 2003; 24(22): 2012-20.
  47. Chiu RC. Adult stem cell therapy for heart failure. Expert Opin Biol Ther 2003; 3(2): 215-25.
  48. Siminiak T, Kalawski R, Fiszer D, Jerzykowska O, Rzezniczak J, Rozwadowska N, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J 2004; 148(3): 531-7.
  49. Galbraith DN. Regulatory and microbiological safety issues surrounding cell and tissue-engineering products. Biotechnol Appl Biochem 2004; 40(Pt 1): 35-9.
  50. Dib N, McCarthy P, Campbell A, Yeager M, Pagani FD, Wright S, et al. Feasibility and safety of autologous myoblast transplantation in patients with ischemic cardiomyopathy. Cell Transplant 2005; 14(1): 11-9.
  51. Dib N, Michler RE, Pagani FD, Wright S, Kereiakes DJ, Lengerich R, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation 2005; 112(12): 1748-55.
  52. Mocini D, Colivicchi F, Santini M. Stem cell therapy for cardiac arrhythmias. Ital Heart J 2005; 6(3): 267-71.
  53. Abraham MR, Henrikson CA, Tung L, Chang MG, Aon M, Xue T, et al. Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation. Circ Res 2005; 97(2): 159-67.
  54. Siminiak T, Fiszer D, Jerzykowska O, Grygielska B, Rozwadowska N, Kalmucki P, et al. Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. Eur Heart J 2005; 26(12): 1188-95.
  55. Ince H, Petzsch M, Rehders TC, Kische S, Chatterjee T, Nienaber CA. [Percutaneous transplantation of autologous myoblasts in ischemic cardiomyopathy]. Herz 2005; 30(3): 223-31.
  56. Kahn J. Myoblast cell therapy shows promise, but safety issues linger. J Interv Cardiol 2006; 19(4): 302-3.
  57. Gavira JJ, Herreros J, Perez A, Garcia-Velloso MJ, Barba J, Martin-Herrero F, et al. Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up. J Thorac Cardiovasc Surg 2006; 131(4): 799-804.
  58. Hagege AA, Marolleau JP, Vilquin JT, Alheritiere A, Peyrard S, Duboc D, et al. Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients. Circulation 2006; 114(1 Suppl): I108-I113.
  59. Zenovich AG, Davis BH, Taylor DA. Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells. Handb Exp Pharmacol 2007; (180): 117-65.
  60. Ohnishi S, Nagaya N. Prepare cells to repair the heart: mesenchymal stem cells for the treatment of heart failure. Am J Nephrol 2007; 27(3): 301-7.
  61. Sherman W. Myocyte replacement therapy: skeletal myoblasts. Cell Transplant 2007; 16(9): 971-5.
  62. McCue JD, Swingen C, Feldberg T, Caron G, Kolb A, Denucci C, et al. The real estate of myoblast cardiac transplantation: negative remodeling is associated with location. J Heart Lung Transplant 2008; 27(1): 116-23.
  63. Menasche P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008; 117(9): 1189-200.
  64. Haider HK, Lei Y, Ashraf M. MyoCell, a cell-based, autologous skeletal myoblast therapy for the treatment of cardiovascular diseases. Curr Opin Mol Ther 2008; 10(6): 611-21.
  65. Menasche P. Skeletal myoblasts and cardiac repair. J Mol Cell Cardiol 2008; 45(4): 545-53.
  66. Veltman CE, Soliman OI, Geleijnse ML, Vletter WB, Smits PC, ten Cate FJ, et al. Four-year follow-up of treatment with intramyocardial skeletal myoblasts injection in patients with ischaemic cardiomyopathy. Eur Heart J 2008; 29(11): 1386-96.
  67. De Muinck ED. Gene and cell therapy for heart failure. Antioxid Redox Signal 2009; 11(8): 2025-42.
  68. Dib N, Dinsmore J, Lababidi Z, White B, Moravec S, Campbell A, et al. One-year follow-up of feasibility and safety of the first U.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAuSMIC study). JACC Cardiovasc Interv 2009; 2(1): 9-16.
  69. Duckers HJ, Houtgraaf J, Hehrlein C, Schofer J, Waltenberger J, Gershlick A, et al. Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial. EuroIntervention 2011; 6(7): 805-12.
  70. Menasche P. [Perspectives in cardiac cell therapy]. Presse Med 2007; 36 Spec No 1: 1S55-8.
  71. Homicz MR, Watson D. Review of injectable materials for soft tissue augmentation. Facial Plast Surg 2004; 20(1): 21-9.
  72. Wong T, McGrath JA, Navsaria H. The role of fibroblasts in tissue engineering and regeneration. Br J Dermatol 2007; 156(6): 1149-55.
  73. Smits PC. Myocardial repair with autologous skeletal myoblasts: a review of the clinical studies and problems. Minerva Cardioangiol 2004; 52(6): 525-35.
  74. Marin-Garcia J, Goldenthal MJ. Application of stem cells in cardiology: where we are and where we are going. Curr Stem Cell Res Ther 2006; 1(1): 1-11.
  75. Mazhari R, Hare JM. Advances in cell-based therapy for structural heart disease. Prog Cardiovasc Dis 2007; 49(6): 387-95.
  76. Menasche P. Skeletal myoblasts as a therapeutic agent. Prog Cardiovasc Dis 2007; 50(1): 7-17.
Journal of Isfahan Medical School
Volume 29, Issue 150 - Serial Number 150
July and August 2011
Pages 1120-1136

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History

  • Receive Date: 19 September 2011
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

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