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

Abstract

While the successful differentiation of human embryonic stem cells into high purity populations of specialized cells is viewed as a major step towards the safety of prospective human transplantation trials, concerns about the possible risks of tumor formation remain. The potential tumorigenicity of transplants derived from embryonic stem cells raises distinctive ethical challenges regarding trial design, evaluation of their risks to potential benefits ratio, population selection, and post-trial subject monitoring. These challenges are examined within the context of foreseen trials for disorders of the central nervous system.

Keywords:

• clinical trials
• ethics
• human embryonic stem cells
• neurodegenerative diseases
• spinal cord injury

Acknowledgments

I thank Françoise Baylis, Ph.D., Frederic Bretzner, Ph.D., Jim Hess, Ph.D., and Tim Krahn for their helpful comments on earlier versions of this manuscript, without suggesting their endorsement of my analysis. This research was funded by the Canadian Institutes of Health Research, MOP 77670, Therapeutic Hopes and Ethical Concerns: Clinical Research in the Neurosciences.

Notes

The author indicates no potential conflicts of interest.

¹Front-runner companies currently developing hESC-based agents for clinical applications include Advanced Cell Technology (California) and Pfizer-backed Institute of Ophthalmology at the University College London for the treatment of macular degeneration, and Novocell (California) for the treatment of diabetes. Advanced Cell Technology has completed pre-IND meetings and is expected to file an application in the near future (Advanced Cell Technology, 2009). The U.K. team is currently applying with the Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a trial. This trial, expected to commence within the next two years, will likely be the second in the world after Geron's to use hESC-based products (Templeton, 2009). The prospect of a trial for diabetes is further away. Aside from a large market potential, the choice of macular degeneration as a target for early trials presents substantial advantages in terms of safety. A very small number of cells may be sufficient to provide clinical benefits, and the needed cells are easy to differentiate and purify. In addition, the eye is relatively isolated from the rest of the body and very easy to monitor for potential emerging adverse events (Stojkovic and Daher, 2009).