BioWorld International Correspondent

PHILADELPHIA - A coordinated effort between industry, government and academia has positioned the UK as a leader in the responsible development of human embryonic stem cells, and researchers now are moving ahead to solve issues involved in GMP production and paving the way for clinical trials.

"We hope in the next year or two we will have a number of embryonic stem cell lines that meet GMP criteria," Harry Moore, co-director of the Centre for Stem Cell Biology at the University of Sheffield, told delegates at the BIO 2005 convention.

Such progress is needed because the therapeutic potential of embryonic stem cells no longer is in doubt. For example, in a research program with the Juvenile Diabetes Research Foundation, Moore's group showed it could produce cells that secrete C-peptide, the precursor of insulin.

"We can create something very similar to an islet in culture, and this gives us the confidence that if we could make enough cells they could be used for therapy," he said. "The problem is we can't use these lines because they are not GMP compliant."

The Sheffield researchers have gathered 70 human embryonic stem cell lines from around the world to compare their fundamental properties and inform the attempts to develop GMP-compliant lines. To date they have established six cell lines with normal karyotypes, four of which were derived using serum-free medium.

The group also is deriving markers that can be used for quality control and quality assurance, including indicators of DNA methylation, protein glycosylation and antibody markers, and is devising techniques to use RNAi to induce differentiation of stem cells without direct genetic intervention.

But GMP compliance depends not only on the minutiae of how the cell lines are differentiated and the conditions in which they are grown, but also on applying appropriate ethical protocols upstream in in vitro fertilization clinics.

That involves rules for ensuring informed consent from embryo and gamete donors for potential commercial exploitation; for maintaining anonymity while allowing researchers to get information about the provenance of embryos and the health status of donors; and agreements on how much information patients should receive on any outcomes related to their donations.

Those moves to produce stem cell lines that will satisfy regulators are in parallel to a focus on translating embryonic stem cell research into the clinic, said Stephen Minger, director of the Stem Cell Biology Laboratory at University College London. Minger is in the thick of the nuts and bolts of deriving embryonic stem cell lines, but he also is collaborating with a number of clinicians working in central nervous system disorders, spinal cord injury, cardiac repair, retinal regeneration, endocrine disorders, hepatic regeneration, joint and bone destruction, and tooth regeneration.

"Stem cell research requires a high level of collaboration and a number of types of different expertise," Minger said. All the major research groups in the UK meet three times a year under the auspices of the Human Embryonic Stem Cell Forum. "There is a great drive to clinical translation," Minger said.

While the debate has focused on regenerative medicine, there is huge near-term commercial potential for using stem cells for human risk assessment in drug development and for testing food additives and other chemicals, according to Tom Shepherd, CEO of CXR Biosciences Ltd. in Dundee, Scotland.

CXR specializes in drug development services, in particular, toxicity testing, and is developing human hepatocytes from embryonic stem cells for use in in vitro toxicity testing.

The cost of drug development is soaring due to compound attrition, with hepatoxicity featuring as a major cause of drug failure. "This is because the animal models are no good," Shepherd said.

"We have produced hepatocyte-like cells that seem to be behaving well," he said. Using human hepatocytes for in vitro testing will have significant advantages over animal testing, Shepherd said. "It can not only measure the toxicity of the compounds itself but also the toxicity of metabolites."

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