Risk of Tumorigenesis in First-in-Human Trials of Embryonic Stem Cell Neural Derivatives: Ethics in the Face of Long-Term Uncertainty

References

• Advanced Cell Technology. (2009). Retinal pigmented epithelial cell program. Available at http://www.advancedcell.com/rpe-program (Accessed: 20 May 2009 ).
   Google Scholar
• Alper , J. 2009 . Geron gets green light for human trial of ES-cell-derived product . Nature Biotechnology , 27 : 213 – 214 .
   PubMed Web of Science ®Google Scholar
• Amariglio , N. , Hirshberg , A. , Scheithauer , B. W. , Cohen , Y. , Loewenthal , R. , Trakhtenbrot , L. , Paz , N. , Koren-Michowitz , M. , Waldman , D. , Leider-Trejo , L. , Toren , A. , Constantini , S. and Rechavi , G. 2009 . Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient . PLoS Medicine , 6 : 221 – 230 .
   Web of Science ®Google Scholar
• Andrews , P. W. , Matin , M. M. , Bahrami , A. R. , Damjanov , I. , Gokhale , P. and Draper , J. S. 2005 . Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: Opposite sides of the same coin . Biochemical Society Transactions , 33 : 1526 – 1530 .
   PubMed Web of Science ®Google Scholar
• Baker, M. (2008). Prepping stem cells for the clinic. Nature Reports Stem Cells, April 10 2008. Available at http://www.nature.com/stemcells/2008/0804/080410/full/stemcells.2008.59.html (Accessed: 30 March 2009 ).
   Google Scholar
• Belmont Report . 1979 . Protection of human subjects: Ethical principles and guidelines for the protection of human subjects of research . Fed Regist , 44 : 23192 – 23197 .
   Google Scholar
• Blum , B. and Benvenisty , N. 2008 . The tumorigenicity of human embryonic stem cells . Advances in Cancer Research , 100 : 133 – 158 .
   PubMed Web of Science ®Google Scholar
• Brederlau , A. , Correia , A. S. , Anisimov , S. V. , Elmi , M. , Paul , G. , Roybon , L. , Morizane , A. , Bergquist , F. , Riebe , I. , Nannmark , U. , Carta , M. , Hanse , E. , Takahashi , J. , Sasai , Y. , Funa , K. , Brundin , P. , Eriksson , P. S. and Li , J. Y. 2006 . Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and teratoma formation . Stem Cells , 24 : 1433 – 1440 .
   PubMed Web of Science ®Google Scholar
• Buckner , J. C. , Brown , P. D. , O'Neill , B. P , Meyer , F. B. , Wetmore , C. J. and Uhm , J. H. 2007 . Central nervous system tumors . Mayo Clinic Proceedings , 82 : 1271 – 1286 .
   PubMed Web of Science ®Google Scholar
• Cloutier , F. , Siegenthaler , M. M. , Nistor , G. and Keirstead , H. S. 2006 . Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm . Regenerative Medicine , 1 : 469 – 479 .
   PubMed Web of Science ®Google Scholar
• Council for International Organizations of Medical Sciences (CIOMS). (2002). International ethical guidelines for biomedical research involving human subjects. Available at www.cioms.ch/frame_guidelines_nov_2002.htm (Accessed: 30 March 2009 ).
   Google Scholar
• Couzin , J. 2009 . Celebration and concern over U.S. trial of embryonic stem cells . Science , 323 : 568
   PubMed Web of Science ®Google Scholar
• Dawson , L. , Bateman-House , A. S. , Mueller Agnew , D. , Bok , H. , Brock , D. W. , Chakravarti , A. , Greene , M. , King , P. A. , O'Brien , S. J , Sachs , D. H. , Schill , K. E. , Siegel , A. , Solter , D. , Suter , S. M. , Verfaillie , C. M. , Walters , L. B. , Gearhart , J. D. and Faden , R. R. 2003 . Safety issues in cell-based intervention trials . Fertility and Sterility , 80 : 1077 – 1085 .
   PubMed Web of Science ®Google Scholar
• Deb , K. D. and Sarda , K. 2008 . Human embryonic stem cells: preclinical perspectives . Journal of Translational Medicine , 29 : 7
   Web of Science ®Google Scholar
• Emanuel , E. J. , Wendler , D. and Grady , C. 2000 . What makes clinical research ethical? . JAMA , 283 : 2701 – 2011 .
   PubMed Web of Science ®Google Scholar
• Edwards, S. (2006). Scrutinizing a stem cell trial. Wired March 29. Available at http://www.wired.com/medtech/health/news/2006/03/70521 (Accessed: 30 March 2009 ).
   Google Scholar
• Erdö , F. , Bührle , C. , Blunk , J. , Hoehn , M. , Xia , Y. , Fleischmann , B. , Föcking , M. , Küstermann , E. , Kolossov , E. , Hescheler , J. , Hossmann , K. A. and Trapp , T. 2003 . Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke . Journal of Cerebral Blood Flow and Metabolism , 23 : 780 – 785 .
   PubMed Web of Science ®Google Scholar
• Food and Drug Administration (FDA). (2006). Guidance for Industry: Gene therapy clinical trials-–Observing subjects for delayed adverse events. Available at http://www.fda.gov/cber/gdlns/gtclin.pdf (Accessed: 30 March 2009 ).
   Google Scholar
• Food and Drug Administration (FDA). (2008a). Briefing Documents: Cellular Therapies Derived from Human Embryonic Stem Cells. Considerations for Pre-Clinical Safety Testing and Patient Monitoring. Available at www.fda.gov/ohrms/dockets/ac/08/briefing/2008-0471B1_1.pdf (Accessed: 30 March 2009 ).
   Google Scholar
• Food and Drug Administration (FDA). (2008b). Transcripts: 45th Meeting of the Center for Biologics Evaluation and Research, Food and Drug Administration. Cellular Therapies Derived from Human Embryonic Stem Cells. Considerations for Pre-Clinical Safety Testing and Patient Monitoring. Available at(-02, -03, -04, -05) http://www.fda.gov/OHRMS/DOCKETS/ac/08/transcripts/2008-0471t1-01.htm (Accessed: 30 March 2009 ).
   Google Scholar
• Geron (2009a). Geron receives FDA clearance to begin world's first human clinical trial of embryonic stem cell-based therapy. Available at http://www.geron.com/grnopc1clearance/ (Accessed: 30 March 2009 ).
   Google Scholar
• Geron, (2009b). Webcast: Geron receives FDA clearance to begin world's first human clinical trial of embryonic stem cell-based therapy. Available at http://www.geron.com/grnopc1clearance/ (Accessed: 30 March 2009 ).
   Google Scholar
• Guillaume , D. J. and Zhang , S. C. 2008 . Human embryonic stem cells: a potential source of transplantable neural progenitor cells . Neurosurgical Focus , 24 : 1 – 7 .
   Google Scholar
• Gruen , L. and Grabel , L. 2006 . Concise review: Scientific and ethical roadblocks to human embryonic stem cell therapy . Stem Cells , 24 : 2162 – 2169 .
   PubMed Web of Science ®Google Scholar
• Hentze , H. , Graichen , R. and Colman , A. 2007 . Cell therapy and the safety of embryonic stem cell-derived grafts . Trends in Biotechnology , 25 : 24 – 32 .
   PubMed Web of Science ®Google Scholar
• International Society for Stem Cell Research (ISSCR). (2008). Guidelines for the clinical translation of stem cells. Available at http://www.isscr.org/clinical_trans/pdfs/ISSCRGLClinicalTrans.pdf (Accessed: 30 March 2009 ).
   Google Scholar
• Joannides , A. J. and Chandran , S. 2008 . Human embryonic stem cells: An experimental and therapeutic resource for neurological disease . Journal of the Neurological Sciences , 265 : 84 – 88 .
   PubMed Web of Science ®Google Scholar
• Keirstead , H. S. , Nistor , G. , Bernal , G. , Totoiu , M. , Cloutier , F. , Sharp , K. and Steward , O. 2005 . Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury . Journal of Neuroscience , 25 : 4694 – 4705 .
   PubMed Web of Science ®Google Scholar
• Kennedy , P. and Rogers , B. A. 2000 . Anxiety and depression after spinal cord injury: A longitudinal analysis . Archives of Physical Medicine and Rehabilitation , 81 : 932 – 937 .
   PubMed Web of Science ®Google Scholar
• Kimmelman , J. 2005 . Recent developments in gene transfer: Risk and ethics . BMJ.com , 330 : 79 – 82 .
   PubMed Web of Science ®Google Scholar
• Kimmelman , J. , Baylis , F. and Glass , K. C. 2006 . Stem cell trials: Lessons from gene transfer research . Hastings Center Report , 36 : 23 – 26 .
   PubMed Web of Science ®Google Scholar
• Kimmelman , J. 2008 . The ethics of human gene transfer . Nature Reviews Genetics , 9 : 239 – 244 .
   PubMed Web of Science ®Google Scholar
• Kishi , Y. , Robinson , R. G. and Forrester , A. W. 1995 . Comparison between acute and delayed onset major depression after spinal cord injury . Journal of Nervous and Mental Disease , 183 : 286 – 292 .
   PubMed Web of Science ®Google Scholar
• Lawrenz , B. , Schiller , H. , Willbold , E. , Ruediger , M. , Muhs , A. and Esser , S. 2004 . Highly sensitive biosafety model for stem cell-derived grafts . Cytotherapy , 6 : 212 – 222 .
   PubMed Web of Science ®Google Scholar
• Levine , R. J. 1988 . Ethics and Regulation of Clinical Research , 2nd , New Haven and London : Yale University Press .
   Google Scholar
• Master , Z. , McLeod , M. and Mendez , I. 2007 . Benefits, risks and ethical considerations in translation of stem cell research to clinical applications in Parkinson . Journal of Medical Ethics , 33 : 169 – 173 .
   PubMed Web of Science ®Google Scholar
• Matzo , M. and Sherman , D. W. 2004 . Gerontologic Palliative Care Nursing , St. Louis , MO : Mosby .
   Google Scholar
• Mathews , D. J. , Sugarman , J. , Bok , H. , Blass , D. M. , Coyle , J. T. , Duggan , P. , Finkel , J. , Greely , H. T. , Hillis , A. , Hoke , A. , Johnson , R. , Johnston , M. , Kahn , J. , Kerr , D , Kurtzberg , J. , Liao , S. M. , McDonald , J. W. , McKhann , G. , Nelson , K. B. , Rao , M. , Regenberg , A. , Siegel , A. W. , Smith , K. , Solter , D. , Song , H. , Vescovi , A. , Young , W. , Gearhart , J. D. and Faden , R. 2008 . Cell-based interventions for neurologic conditions: Ethical challenges for early human trials . Neurology , 71 : 288 – 293 .
   PubMed Web of Science ®Google Scholar
• National Institutes of Health (NIH). (2003). Guidance on Informed Consent for Gene Transfer Research. Available at http://oba.od.nih.gov/oba/rac/ic/index.html (Accessed: 30 March 2009 ).
   Google Scholar
• National Institutes of Health (NIH). (2009a). Assessing human stem cell safety. In Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services. Available at http://stemcells.nih.gov/info/scireport/chapter10 (Accessed: 20 March 2009 ).
   Google Scholar
• National Institutes of Health (NIH). (2009b). Brain and spinal tumors. Hope through research. Available at http://www.ninds.nih.gov/disorders/brainandspinaltumors/detail_brainandspinaltumors.html (Accessed: 30 March 2009 ).
   Google Scholar
• Park , C. H. , Minn , Y. K. , Lee , J. Y. , Choi , D. H. , Chang , M. Y. , Shim , J. W. , Ko , J. Y. , Koh , H. C. , Kang , M. J. , Kang , J. S. , Rhie , D. J. , Lee , Y. S. , Son , H. , Moon , S. Y. , Kim , K. S. and Lee , S. H. 2005 . In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons . Journal of Neurochemistry , 92 : 1265 – 1276 .
   PubMed Web of Science ®Google Scholar
• Pollack , A. 2009 . FDA approves a stem cell trial . New York Times , January : 23
   Google Scholar
• Przyborski , S. A. 2005 . Differentiation of human embryonic stem cells after transplantation in immune-deficient mice . Stem Cells , 9 : 1242 – 1250 .
   Web of Science ®Google Scholar
• Rao , M. 2008 . Scalable human ES culture for therapeutic use: Propagation, differentiation, genetic modification and regulatory issues . Gene Therapy , 15 : 82 – 88 .
   PubMed Web of Science ®Google Scholar
• Roy , N. , Cleren , C. , Singh , S. , Yang , L. , Beal , M. and Goldman , S. 2006 . Functional engraftment of human ES cell–derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes . Nature Medicine , 12 : 1259 – 1268 .
   PubMed Web of Science ®Google Scholar
• Scott , C. T. 2008 . Stem cells: New frontiers of ethics, law and policy . Neurosurgery Focus , 24 : 1 – 4 .
   Web of Science ®Google Scholar
• Stojkovic , M. and Daher , S. 2008 . Celebrating 10 years of hESC lines: An interview with Peter Andrews . Stem Cells , 27 : 4 – 6 .
   Web of Science ®Google Scholar
• Song , J. , Lee , S. T. , Kang , W. , Park , J. E. , Chu , K. , Lee , S. E. , Hwang , T. , Chung , H. and Kim , M. 2007 . Human embryonic stem cell-derived neural precursor transplants attenuate apomorphine-induced rotational behavior in rats with unilateral quinolinic acid lesions . Neuroscience Letters , 423 : 58 – 61 .
   PubMed Web of Science ®Google Scholar
• Templeton , S. K. 2009 . Blind to be cured with stem cells . Sunday Times , April 19
   Google Scholar
• Thomson , J. A. , Itskovitz-Eldor , J. , Shapiro , S. S. , Waknitz , M. A. , Swiergiel , J. J. , Marshall , V. S. and Jones , J. M. 1998 . Embryonic stem cell lines derived from human blastocysts . Science , 282 : 1145 – 1147 .
   PubMed Web of Science ®Google Scholar
• Vogel , G. 2005 . Ready or not? Human ES cells head toward the clinic . Science , 308 : 1534 – 1538 .
   PubMed Web of Science ®Google Scholar
• Yang , D. , Zhang , Z. J. , Oldenburg , M. , Ayala , M. and Zhang , S. C. 2008 . Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats . Stem Cells , 26 : 55 – 63 .
   PubMed Web of Science ®Google Scholar
• Zarin , D. A. and Tse , T. 2008 . Moving toward transparency of clinical trials . Science , 319 : 1340 – 1342 .
   PubMed Web of Science ®Google Scholar
• Zhang , S. C. , Wernig , M. , Duncan , I. D. , Brüstle , O. and Thomson , J. A. 2001 . In vitro differentiation of transplantable neural precursors from human embryonic stem cells . Nature Biotechnology , 19 : 1129 – 1133 .
   PubMed Web of Science ®Google Scholar