Despite the continuing hype surrounding the potential for therapeutics derived from human embryonic stem cells (hESCs), the pharmaceutical industry has largely remained on the sidelines, content to establishing research alliances with universities, institutes, and small biotechs. Instead, Big Pharma’s abiding interest in hESCs lies in developing drug screening and other novel assays to accelerate the drug discovery process.
Unlike therapeutics, which are likely several years distant, screening efforts may be closer to reality. If so, the benefits could be immense. Currently, nearly a third of all drug development candidates fail due to cardiotoxicological problems, with up to three quarters of cardiotoxicology and hepatotoxicity problems remaining undetected until preclinical and early-stage trials. Earlier detection of these problems could reduce the time and expense of drug discovery and also as mitigate potentially harmful patient exposure in clinical trials.
In the latest development in drug screening, Roche has forged a three-to-five year collaboration with Massachusetts General Hospital and Harvard University to use cell lines derived from healthy volunteers and patients with various diseases to screen drug candidates in its compound library for efficacy, safety, and toxicology profiles. The $20-million collaboration signed earlier this year will focus initially on metabolic disorders and cardiovascular disease. Roche will also make clinical development milestone payments for drug candidates discovered through stem cell disease models.
Four widely-used human embryonic stem cell (hESC) lines were reapproved for ongoing use in federally funded research by the National Institutes of Health (NIH) in late April after completing detailed application and documentation processes.
The WiCell Research Institute’s H9 (WA09) human embryonic stem (ES) cell line and three of the original “Wisconsin” lines, H7 (WA07), H13 (WA13) and H14 (WA14) have been used in hundreds of federal research projects, as allowed under the Bush administration. The lines were not grandfathered for federal funding eligibility under the new NIH approval guidelines adopted last July.
The application process for H7, 9, 13 and 14 took longer than the H1 line, derived from an embryo donated through a Wisconsin IVF clinic, because the embryos for these lines were donated through a medical center in Israel.
“With these embryos originating in Israel more than a decade ago, it took significant time and effort to locate, gather and translate the documents from Hebrew to English, so we could complete the application,” stated Erik Forsberg, executive director of WiCell, a private nonprofit affiliated with UW-Madison.
The hope is that hESC-derived assays will provide more accurate screens because they use actual target tissue (such as heart and liver) as opposed to current platforms, which employ animal and non-target human cells. “This technology is like having a disease in a test tube, and being able to test possible effects of drugs on ‘virtual’ patients [is] translational medicine at its best,” said Jean-Jacques Garaud, MD, global head of Roche Pharma Research and Early Development.
The collaboration is one of several for Roche. Last June, the company signed a $10-million, two-year agreement with the Paris-based Institute for Stem Cell Therapy and Exploration of Monogenic Diseases. Roche will use I-STEM’s neuronal stem cell proliferation techniques to screen its libraries for molecules having potential to treat neurodegenerative diseases. And in July, the company expanded its agreement with Cellular Dynamics Inc. (Madison, Wis.) to test drug development candidates for cardiotoxicity potential through various cell characterization, toxicological, and electrophysiological tests.
Roche is far from being the only player in the hESC screening field. Last year, GE Healthcare and Geron Corp. agreed to jointly develop and commercialize cellular assays derived from hESCs for in vitro drug candidate screening. The cell lines used are derived from those listed in the National Institutes of Health stem cell registry. “The expertise that we have developed in scalable manufacturing and differentiation of hESCs to specific cell types is directly applicable to the production of these cells for drug discovery,” said David J. Earp, PhD, JD, Geron’s senior vice president of business development and chief patent counsel.
Of course, several Big Pharmas are active in the race to develop hESC-based therapeutics. Among them is Pfizer, which established a Regenerative Medicine research unit in 2008. “We will be optimizing the production of cells that could, one day, be used for therapeutic purposes,” said Ruth McKernan, PhD, Pfizer Regenerative Medicine’s chief scientific officer at the time. Pfizer Regenerative Medicine, based in Cambridge, Mass. and in Cambridge, UK, employs about 70 scientists. The US team focuses on heart disease, diabetes, and cancer while the UK team focuses on therapies for vision and hearing.
Pfizer last year signed a licensing agreement with the Wisconsin Alumni Research Foundation (WARF) to conduct research on and commercialize therapies from WARF’s seminal hESC lines. In 2008, Pfizer entered into a non-exclusive, two-year collaboration with San Diego-based Novocell Inc. for access to the company’s proprietary pancreatic progenitor cells derived from hESCs. Novocell had received financing in 2007 from Johnson & Johnson and other investors to support preclinical development of diabetes and other disease cell therapies.
Recently, there have been some encouraging signs in the quest for hESC-derived therapeutics. In January, researchers at the University of California-San Diego (UCSD) announced they had created human stem cells genetically modified to include specific disease genes 20% of the time in contrast to the previous benchmark of inclusion only 1% of the time. Using what they called “bacterial artificial chromosomes” the researchers were able to selectively transfer the p53 gene, whose defects have been implicated in many cancers. They also transferred the ATM gene, whose defects cause ataxia telangiectasia, a rare disorder also associated with cancer.
But as most scientists well know, the road to discovery is often strewn with bureaucratic potholes. The Obama Administration’s well-publicized efforts to expand federal funding for hESC research has been stymied, at least temporarily, by the very regulations intended to streamline them. The new guidelines, which Obama signed in March 2009, expand the number of cell lines eligible for federal funding but also require detailed consent documents from donors—a time consuming process, particularly for cell lines derived more than a decade ago.
Despite occasional pitfalls, funding efforts continue. In March, officials in California broke ground on a $115-million “collaboratory” that will house interdisciplinary stem cell scientists from the University of California-San Diego, the Salk Institute, Scripps Research Institute and the Sanford-Burnham Medical Research Institute.
“This new core laboratory will apply an array of the most promising technologies in the world for controlling stem cell differentiation, delivering stem-cell based therapies, scaling up cell production, and engineering replacement tissues,” said Andrew McCulloch, PhD, chair of UCSD’s Department of Bioengineering.
About the Author
Contributing editor Ted Agres, MBA, is a veteran science writer in Washington, DC. He writes frequently about the policy, politics, and business aspects of life sciences.
This article was published in Drug Discovery & Development magazine: Vol. 13, No. 4, May 2010, pp. 6-7.
Filed Under: Drug Discovery