RNAi, embryonic stem cells, and technological prematurity

During the Bush administration, the US scientific community, numerous biotech companies, “disease organizations”, many politicians, and families affected by diseases such as juvenile diabetes, spinal cord injuries, and neurodegenerative diseases, deplored the administration’s restrictions on use of Federal funds for human embryonic stem (hES) cell research. Many predicted that countries with fewer restrictions, such as the UK, would far outdistance the United States in stem cell research, and in its applications to regenerative medicine.

In March of this year, the new Obama administrations lifted many restrictions on hES cell research. However, it is clear that the US did not significantly fall behind countries that did not have the Bush-era restrictions in place during the past eight years. Why not? It is because hES cell research constitutes a scientifically premature technology.

A field of biomedical science is said to be scientifically or technologically premature when despite the great science and exciting potential of the field, any practicable therapeutic applications are in the distant future, due to difficult hurdles in applying the technology. Thus researchers in countries not hampered by the former US restrictions were unable to capitalize on their “head start” as was feared.

On January 22, I gave a presentation at the Center for Business Intelligence (CBI) conference “Executing on the Promise of RNAi” in Cambridge MA. My presentation, “The Therapeutic RNAi Market – Lessons from the Evolution of the Biologics Market”, compared the field of monoclonal antibody (MAb) drugs to that of RNAi drugs. Despite the high level of investment in therapeutic RNAi, the formation of numerous biotech companies specializing in RNAi drug development, and the strong interest of Big Pharma in the field, there is still not one therapeutic RNAi product on the market. Researchers also see significant hurdles to the development of RNAi drugs, especially those involving systemic drug delivery. As a result, many experts believe that therapeutic RNAi is scientifically premature.

MAbs currently represent the most successful class of biologics. However, the therapeutic MAb field went through a long period of scientific prematurity, from 1975 through the mid-1990s. Several enabling technologies, developed from the mid-1980s to the mid-1990s, were necessary for the explosion of successful MAb drugs, from the mid-1990s to today. Similarly, many companies and academic laboratories are hard at work developing enabling technologies to catalyze the development of the therapeutic RNAi field. Among researchers active in developing these enabling technologies were several speakers at the CBI conference, from such companies as Alnylam, RXi, Dicerna, Calando, miRagen, Santaris, and Quark.

With respect to hES cells, researchers (including American researchers) have been hard at work on developing enabling technologies to move that field up the technology development curve. Notably, within the last three years, researchers in Japan, the US, Canada, and other countries have developed the new field of induced pluripotent stem (iPS) cells. This field is based on a set of technologies in which adult cells are reprogrammed, via insertion of four (or fewer) specific genes, into pluripotent cells that resemble embryonic stem cells. This approach not only gets around many of the ethical objections to the use of embryo-derived hES cells, but also potentially puts stem cells into the hands of many more researchers, who do not have ready access to human embryos. Moreover, iPS technology has the potential to enable researchers to construct patient-matched stem cells for cellular therapies, thus eliminating the prospect of immune rejection of transferred cells.

The iPS cell field was reviewed in a News Feature in the 23 April 2009 issue of Nature. As discussed in this review, researchers have been concentrating on developing the technology, for example reprogramming cells by using non-integrating or excisable vectors, or even with no inserted genes at all (e.g., combinations of small-molecule drugs and proteins). One researcher, Rudolf Jaenisch of MIT and the Whitehead Institute, said in the article that research in the iPS field has so far been all about technology. At some point in the near future, Jaenisch believes that the field will shift to considering scientific questions such as mechanisms of reprogramming and of cellular differentiation and dedifferentiation.

A few potential hES cell-based therapies are making their way to the clinic. In January, Geron announced that the FDA had cleared the company’s Investigational New Drug application (IND) for human clinical trials of an hES cell-based therapy for spinal cord repair. Pfizer, in collaboration with researchers at University College, London, is working to develop a hES cell-based therapy for age-related macular degeneration (AMD), a leading cause of blindness. This will involve treatment of patients with retinal pigment epithelial cells derived from hES cells. The researchers anticipate beginning clinical trials within two years. Especially in the case of the hES-based spinal cord therapy, many researchers see major pitfalls, which may result in clinical failure. This situation is typical for initial applications of an early-stage or premature technology.

Early-stage or premature technologies often still have great value in the research laboratory, including enabling research breakthroughs that can lead to new therapies. For example, MAb technology, even in its earliest days, enabled researchers to discover receptors that are key to the activity of cells of the immune system and of tumor cells. This resulted in enormous breakthroughs in immunology and in cancer biology, with eventual applications to the development of successful anti-inflammatory, anti-HIV/AIDS, and anti-tumor drugs. RNAi technology has become a mainstay of target validation and pathway studies in drug discovery. Similarly, researchers expect that hES cell technology—and especially iPS cell technology—will provide breakthrough tools for drug discovery researchers. This may well happen far in advance of the development of hES/iPS-based cellular therapies.