An ethical division

It has been estimated that stem cell therapies will generate sales of USD 700m by 2010, and exceed USD 8.5bn by 2016. The overall stem cell marketplace, primarily composed of tools, reagents, technologies and services, is expected to surpass USD 35m in 2007, and continue to rise.

Stem cells can generally be classified as embryonic or adult. Embryonic stem cells have an unlimited capacity for self-renewal and can differentiate into virtually any cell type. Adult stem cells are tissue-specific, have limited self-renewal capability, and generally can only differentiate into specialised (mature) cells of the tissue in which they reside.

• Replacement cell therapy in a number of therapeutic/disease areas - it has been suggested that umbilical cord blood-banking at the time of delivery will provide a source for future transplantation
• Research tools to model neurodegenerative and other diseases
• Models for cancer stem cells
• Study aids for autoimmune diseases
• A means to better understand embryonic development.

A major limiting factor in this effort is the restrictions placed on research by governmental regulations because of ethical concerns about the use of human embryonic stem cells (hESCs). The relatively permissive regulatory environment set out by the UK government, has resulted in this country becoming a global leader in the field of stem cell research. Supporting research from all sources, including adult, foetal and embryonic stem cells, UK scientists have had the freedom to progress this medical frontier, opening up enormous opportunities for the development of novel treatments for disease and injuries.

In contrast, the US government has not adopted this liberal regulatory approach, and has generally refused to fund research on hESCs. Most US states currently only support the use of adult stem cells, or prohibit all research. The general consensus is that public opinion in the US does not wholly match that of its government and scientists and researchers are hoping that there will eventually be a relaxation of these policies. With US USD 3bn stem cell funding presented to the state of California via a 2004 bond measure, it has been suggested this state may catch-up with the UK at some point.

Regulations also vary among the European countries, with some taking a more restrictive view than others. In Germany, for example, strong restrictions are placed on the use of hESCs in research, and as they are only able to use animal models, many scientists feel they are simply 'setting the platform' for other countries. This complex regulatory structure has by no means prohibited the progress of stem cell product development however, and several companies are already beginning to explore the commercial opportunities that present themselves in this still highly-controversial arena.

Geron is the world leader in hESC-based therapeutics, with GRNOPC1, indicated for acute spinal cord injury, poised to enter the clinic in the first quarter of 2008. GRNOPC1 contains oligodendroglial progenitor cells (OPCs). Oligodendroglia are cells that produce myelin - the insulating sheath that covers nerve fibres.

Progenitor cells are similar to stem cells but some of their properties are more limited. OPCs adapt to the local micro-environment they are placed in and begin to fix the specified lesion site. Studies that will enable Investigational New Drug (IND) filing are relatively advanced. Animals models have been monitored for more than one year after injection with no evidence of teratoma (tumour). Geron is on target to file an IND at the end of 2007.

Also in the pipeline is GRNCM1, currently undergoing preclinical investigation for the potential treatment of heart failure. This therapy comprises cardiomyocytes (heart muscle cells) derived from hESCs. Research has shown that these cells respond normally to cardiac drugs and to ventricular electrophysiology - in which various techniques are employed to test their reponse to electrical impulses. Magnetic resonance imaging (MRI) has shown that they can improve systolic function - the contraction of the chambers of the heart that pump blood - in animal models.

Proof of concept has been established for another product, GRNIC1, that comprises pancreatic islet cell clusters similar to the cells in the pancreas - called the islets of Langerhans - that produce insulin. These cells been shown to produce insulin and glucagon and are currently under investigation for the potential treatment of diabetes.

Germany-based company t2cure was initially set up with the aim of commercialising therapies originating from research at Johann Wolfgang Goethe University. The company has been developing therapies from autologous bone marrow - ie bone marrow cells derived from the same individual they are destined to treat. In particular they have been investigating potential therapies from endothelial progenitor cells. These are primitive cells made in the bone marrow that are carried by the blood and have a role in repairing damaged blood vessels.

These particular cells are being investigated for the potential treatment of

• myocardial infarction (as t2c-001-AMI)
• ischaemic heart disease (as t2c-001-CHD)
• congestive heart failure (as t2c-001-SW)
• peripheral arterial occlusive disease (as t2c-002-PAOD)
• dilative cardiomyopathy (as t2c-001-DCM)
• diabetic neuropathy (as t2c-002-NP and t2c-003).

By July 2007, t2cure's lead product t2c-001-AMI was in phase II trials, and is said by the company to be on the verge of entering phase III clinical trials for severe infarcts. Phase I/II studies are ongoing for the other indications listed above, with phase II studies expected in the near future in critical limb ischaemia, peripheral arterial occlusive disease (PAOD) and diabetic polyneuropathy.

Cellerix is developing expanded autologous adipose (fat)-derived stem cells for the potential treatment of complex perianal fistula, with and without Crohn's disease. In Europe in February 2007, a comparative, randomised, single-blind, phase III trial was initiated in subjects with complex perianal fistulas without inflammatory bowel disease.

At that time, the study, with an expected total enrolment of 207 patients, was anticipated to complete in July 2008. In July 2007, the company expected this injectable therapy, referred to as Cx-401, to reach the market by 2009 or 2010. The company is also looking to outlicense the therapy in Japan, and other locations outside Europe.

Despite preclinical studies demonstrating good safety and efficacy data in a variety of tested models, and many late-stage products disclosing positive clinical data, researchers must continue to approach stem cell-related therapies with caution, and not be tempted to rush any product to the clinic for the sake of market opportunities.

Regulatory restrictions are clearly affecting the rate of progress in this field, but in time stem cell therapies may come to change the way we view modern medicine.

The Author
Angela Elliott is an editor in the drug information department at Thomson Scientific. This article is based on data from Thomsonpharma