Stem Cell Technologies…

Stem cell technology - Delivering the promise

The promise of stem cell technology as a tool for drug discovery, drug development, and as a therapeutic modality is no longer in the future but part of contemporary health care. The speed which stem cells have been integrated into biomedical product development has surprised many, but stem cells in the form of bone marrow transplants have been around for several decades in medical practice.

Most drug discovery programs now use functional, cell-based assays for target hit identification and lead optimization because of the desire to utilize the scientific understanding of signaling pathways. This has resulted in a capability to probe more complex targets and seek target modulation, rather than complete inhibition. Pharmaceutical companies have also employed stem cell technology for drug discovery and testing for over ten years. Stem cells may help us understand the complexity of human disease by studying cells as they become more differentiated, making nerves, skin, cartilage, bone, and brain. Drug developers hope that characterizing the signals and mechanisms of cell differentiation may yield information about how diseases arise and suggest new strategies for therapy. New medications are now tested for safety on specialized cells generated in large numbers from stem cell lines—reducing the need for animal testing—and cancer stem cell lines are used to screen potential anti-tumor drugs.

Thus, there are considerable efforts in adopting stem cell assays for drug discovery, since stem cells can differentiate into specific cell types that may not be available from human sources. Also, many available normal human cells have not been very good at predicting side effects of newly discovered drugs as they enter the pipeline. It still must be proved that, in each example, differentiated cells from stem cells are equivalent to the normal or target cells and can be validated as a drug screening tool. Critical areas of drug screening include cardiotoxicity, mutagenicity, and immunogenicity.

Cell-based assays formats play a role in testing compounds for effects on proliferation and screening for inhibitors or modulators of cell growth. In addition, the effects of modulators of stem cell self-renewal will help define stem cells and their potential cell fates during differentiation. Studies to characterize both the natural and desired functioning of stem cells, progenitor cells and differentiated cells will be crucial. This focus on stem cell biology has yielded innovative technologies and cell-based tools for leading-edge research. This will hopefully translate into comprehensive drug discovery and development programs which can bring new medicines to market faster and more cost-effectively. These advances should also translate into more robust manufacturing processes that supply novel therapeutics to clinical development programs with high efficiency.

The use of stem cells for large-scale discovery and testing efforts requires a very large number of cells for the rapid and automated methods of today. The need for a large number of differentiated cells, which mimic the human condition, is an opportunity for companies to supply tools and services for the new approaches to cost-effective drug discovery. Sometimes cells are supplied as frozen stocks or sometimes ready-to-use in high throughput motifs. Contract manufacturing companies, such as Paragon Bioservices, are actively involved in addressing this need.

Many companies have developed unique stem cell technologies and are now relying on service companies to produce and distribute these tool platforms to a wide range of users. Vivo Biosciences Inc has developed a novel human biomatrix system for cultivating human stem cells (e.g. derived from adipose, CNS and MSC) for long-term growth and differentiation studies in both 2D and 3D bioscaffold culture. This approach is in development for use in real-time cell based assays for the xCELLigence System, co-developed by Roche-ACEA.

In 2006, scientists made more news in stem cell research when they identified conditions that would allow some specialized adult cells to essentially be re-programmed genetically to assume a cell-like state, by being forced to express genes for maintaining the defining properties of embryonic stem cells. This type of stem cell is called induced pluripotent stem cells (iPSCs). Like embryonic stem cells, iPSCs are types of stem cells made in the lab (while adult stem cells naturally occur in the human body). Since they are obtained from the patient’s own cells (such as from skin) the ethical issues that plagued human embryonic stem cells are avoided. It is widely believed that iPS cells have the greatest potential for drug discovery and patient therapies.

Testing the toxicity of pharmaceutical candidates in lab animals to support the safety for human clinical trials is notoriously unreliable. Often compounds that appear safe in rodents prove to be toxic in humans. In order to predict toxicity in cell models, many investigators are using embryonic and somatic progenitor cells to monitor the behavior of stem cells exposed to new compounds via disruption of cell-to-cell interactions and interference with expected development or differentiation. Using embryonic stem cells or iPS cells to create human heart cells could be a viable and scientifically exciting alternative to animal testing—saving precious time spent on the wrong drug candidates.

Pro-arrhythmia (development of cardiac arrhythmias as a pharmacological side effect) has become the single most common cause of the withdrawal or restrictions of previously marketed drugs. The development of new medications, free from these side effects, is hampered by the lack of an in vitro assay for human cardiac tissue. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) assessed with a combination of single cell electrophysiology and microelectrode array (MEA) mapping can serve as a novel model for electrophysiological drug screening, according to Caspi,et al. (Stem Cells Dev. 2009 18(1):161-72).

Cellular Dynamics has the ability to generate induced pluripotent stem cell (iPSC) lines from blood samples from hypertensive patients. The iPSC lines can then be differentiated into ventricular heart cells for use in genetic studies. Differentiated iPSC lines may enable a new level of research into the genetics and mechanisms of certain diseases that previously has not been possible—due to the unavailability of primary human cardiomyocytes for functional studies.

Making stem cells from the skin of adults rather than embryos also makes it much easier to create cell lines that are ethnically diverse, letting researchers better judge the safety and effectiveness of drugs on a wide range of people. As reported in 2010 by Waters in Bloomberg Business Week, Roche Holding AG scientists tracked the changes in the beating of heart muscle made from iPS cells exposed to an anti-cancer compound and duplicated the side effect previously only seen in patients. The experiment showed that human tissue grown from stem cells can mimic the side effects of medicines that is seen in people. Large pharmaceutical companies are using stem cells to test experimental drugs in an effort to dramatically reduce the cost and risk of the discovery process, which can cost over a billion dollars to produce just one new medicine. More evidence that IPS cells can create heart cells for short-cut drug testing came when the Roche team used them to confirm cardiac toxicity from an antiviral medication that it had been developing.

The outlook for regenerative medicine is bright. Companies are poised to replenish their technology pipelines with developing stem cell science from research universities and early stage biotech. The stem cell market was estimated to be $21.5 billion globally in 2010 and is forecast to reach $63.8 billion by 2015—including both tools and therapeutics. The knowledge gained in drug development has been integrated with new programs for cell therapy and combination drug and cell therapies. Many large pharmaceutical companies are developing internal and external regenerative medicine programs—including Pfizer, Johnson & Johnson, Shire, and GlaxoSmithKline. Some of this expansion is based on knowledge gained by employing stem cell technology in the drug discovery process; others, like Shire, are acquiring commercial stage companies, like Advanced Cell Technologies.

Stem cells are key to replacing cells lost in degenerative diseases and for repairing cells in damaged tissue, similar to organ transplants of the past. Stem cells or their differentiated cell products offer a probable and manufacturable source of replacement cells to treat diseases including Parkinson's, stroke, heart disease and diabetes. There are many companies involved in regenerative medicine. These cell therapy companies include Aastrom Biosciences, Cellerant, Geron, StemCells, and ViaCyte. In addition, many companies supply the products and services that support research and development, such as Life Technologies, Sigma-Aldrich, Cellular Dynamics International, IPierian and ViaCord.

Mesenchymal stem cells (MSCs, also known as bone marrow stromal cells or skeletal stem cells) are multipotent stem cells that can differentiate into chondrocytes (cartilage cells), osteoblasts (bone cells) or adipocytes (fat cells)—making them ideal candidates for tissue engineering. MSCs can contribute to the regeneration of bone, cartilage, muscle and tendons. It has also been shown that—when transplanted systemically into animals—they are able to migrate to the sites of the injury. Scientists are currently examining the potential of generating healthy heart muscle cells in the laboratory and then transplanting those same cells into patients with chronic heart disease.

While progress in this area is exciting, more work remains in both process and clinical development. One of the critical factors limiting growth of the cell-based therapy industry is the lack of expertise in product development and specialized manufacturing that will be required to bring these products to market. In many ways, the level of complexity for cell products is higher than for biologics. The need to supply a large number of highly characterized and documented cells exists on an international basis. Medical tourism is increasing; patients are seeking treatments for life threatening diseases that are currently not approved for sale in the US. In addition, there is a need for the many cells that are being administered under approved experimental clinical trials internationally.

This is a perfect niche for contract manufacturing companies to support development and clinical supply for regenerative medicine companies. Companies such as Lonza, Progenitor, and Paragon Bioservices, Inc. all offer contract services to drug and regenerative medicine companies. Use of outsourced suppliers for stem cell products fits with current pharmaceutical company strategy to focus internal resources on core capabilities and outsource pre-clinical and clinical stage manufacturing. Recognizing all of the potential in the field of stem cell therapies and the possibility of finding solutions for these public health imperatives, UMB’s Center for Stem Cell Biology and Regenerative Medicine and Paragon Bioservices, Inc. recently created a stem cell initiative to explore how they could advance the scientific research in this exciting field, apply those discoveries to patient care and directly affect human health and disease. This public-private partnership is for the development and manufacturing of stem cell therapies. The Stem Cell Technology Consortium is openly seeking wider participation from multiple universities, State and Federal agencies, and private companies.