Mar 11 2013

The Dawn of a New Clinical Paradigm in the Land of the Rising Sun

A major milestone in the use of stem cells in human therapies was reached in February of 2013.  An ethics committee has authorized the first in-human study utilizing induced pluripotent stem cells (iPSCs) in the treatment of a human disease at the Kobe City Medical Center General Hospital in Japan.  A team led by Dr. Masayo Takahashi is proposing to generate iPS cells, differentiate them into cells normally found in the eye, and use them to repopulate the retinas of patients suffering from macular degeneration, a condition that can lead to blindness.  Dr. Takahashi’s group has successfully performed the procedure in animal models and is now moving to the clinic.  Guidelines for the use of human stem cells in clinical research were adopted by the Ministry of Health, Labor, and Welfare (MHLW) in Japan in July 2006 and were revised in November 2010.  The revision of the guidelines made specific mention of iPSCs and so Japan has been preparing the regulatory framework for just such a study.

iPSCs were first described in a 2006 paper from the laboratory of Dr. Shinya Yamanaka.  Dr. Yamanaka would later share (with Dr. John Gurdon) the 2012 Nobel Prize for Physiology or Medicine for his work on iPSCs.  Dr. Yamanaka’s group at the University of Kyoto successfully reprogrammed adult mouse fibroblasts (which are connective tissue cells, frequently isolated from skin but found throughout the body) to a pluripotent stem cell-like state.  Because of their undifferentiated state, iPSCs can be manipulated to form a variety of other cell types, from heart cells to retinal pigmented epithelial cells (the cell type Dr. Takahashi is hoping to replace in her patients).  These iPSCs have many of the properties of embryonic stem cells but avoid the potential ethical concerns raised by the manipulation human embryos.  It should be noted that Japan’s stem cell guidelines still specifically prohibits the use of human embryonic stem cells in clinical research until standards are established for research using human embryos.  In addition to fewer ethical concerns with iPSCs, these cells also have some medical benefits.  Because they can be derived from adult fibroblasts, it is possible to derive iPSCs from an individual for use in their own medical treatment.  Using these autologous cells potentially mitigates the issue of tissue rejection.

With characteristics like those, it seems like iPSCs should be a gold mine for new medical treatments.  However, there are real and serious concerns with the clinical use of iPSCs.  One major concern within the medical and scientific community stems from the process by which iPSCs are made.  iPSCs are derived by inserting genes from four gene families (Oct3/4, Sox, Myc, and Klf) into a differentiated cell thereby reprogramming the cell to a less differentiated state.  Concern arises from the techniques being used to insert the genes into the cells.  Early generation iPSCs were created using retroviral insertion of the genes into the genome of the cell.  The insertion of the genes leads to two concerns.  The first concern is that integration of the viruses might disrupt important genes such as tumor suppressors, leading to cancer or other disease states.  These concerns have largely been assuaged by new techniques using non-integrating viral based, non-viral DNA based, RNA based, and protein based methods.

The second issue with iPS cells has to do with the genes used to convert the cells to iPS cells.  Both the Myc and Klf family of proteins are oncogenes, the genes that drive cancer.  Therefore, there is a valid concern that placing cells expressing those genes into human subjects will result in cancers developing from the transplanted cells.  This concern is highlighted by the fact that early experiments by Dr. Yamanaka’s group reported that 20% of the offspring of mice created using iPS cells eventually developed tumors, presumably due to reactivation of the retrovirally inserted Myc gene.  The use of oncogenes in the generation of iPSCs is one of the most concerning issues with regards to the potential use of iPS cells in the treatment of human disease.  However, use of the methods mentioned above (non-integrating viruses, non-viral DNA based, RNA based, and protein based methods) avoid this problem to some extent.  Because there is usually no integration of the oncogenes into the genome of the cell, they cannot be reactivated later in the cell’s lifecycle.  Presumably, Dr. Takahashi’s group has carefully analyzed their method for deriving iPS cells and differentiating them to retinal cells to avoid these dangers.  Had they not, the ethics committee would not have authorized a study in human subjects.

In conclusion, the ethics committee authorization of the study does not constitute a regulatory go‑ahead for Dr. Takahashi’s group.  The study still must be reviewed and approved by the MHLW before subjects can be enrolled and treated with the cells.  The MHLW does, as mentioned previously, have guidelines for how such a study should be designed and carried out.  Therefore, if this study conforms to their guidelines, it stands a chance of being authorized by the ministry.  The completion of a successful human trial using iPS cells would open the door to future trials for other indications and could revolutionize regenerative medicine.  The field of pluripotent stem cells, which is just over 30 years old, is a dynamic and quickly evolving area of science.  You can be sure regulatory agencies around the world will be watching.

This is a post by Nick Osborne, Ph.D.  Nick is a Scientist at Cato Research