The UK Stem Cell Foundation (UKSCF) and the Multiple Sclerosis Society joined forces to accelerate the transfer of stem cell science into the clinic to help patients with multiple sclerosis (MS). Up to £1 million of seed funding is to be made available to applicants starting in September. The hope is to get Phase I/II trials of stem cells in MS under way over the next year or so, with initial results expected in 2012.
This is the first disease-specific collaboration for UKSCF, whose mission is to fund the gap between promising stem cell research and clinical trials. It was announced at a special meeting of the London Regenerative Medicine Network (LRMN) on January 14. “MS and advanced stem cell-based therapies—an ABC guide” was the first of a series of new disease-themed meetings to be hosted by LRMN.
“Everyone thinks there is potential for stem cell therapy in MS, but there have been some studies of dubious worth,” noted Mary Archer, UKSCF trustee and chairman of Cambridge University Hospitals NHS Foundation Trust. “Benefit will only be seen from long-term clinical trials. There is no shortcut, but we are seeking to accelerate the process by joining with the MS Society.”
Stem cell therapies for MS aim to prevent or repair the demyelination of nerve fibers, which is the hallmark of the disease. Two different approaches were described at the LRMN meeting. Professor Robin Franklin, director of the MS Society Cambridge Centre for Myelin Repair, explained that a major problem in MS is that the inherent regenerative process, which would otherwise remyelinate nerve fibers, is not sustained. Therapy could be based on either transplanting myelinogenic oligodendrocytes into the patient or on promoting remyelination by endogenous neural stem cells (NSCs).
Targeting the Wnt Pathway
As long ago as 1993, Franklin and colleagues were able to show remyelination in animals by transplanting NSCs. “We thought we were not far from transplantation, but there was a problem in obtaining cells from humans.” It was not until 2008 that Steve Goldman of the University of Rochester Medical Center showed that human NSCs can remyelinate the entire brain in a mouse model of a genetic demyelinating disease.
MS, however, is not genetic. It is an autoimmune disease, and transplanted cells are not likely to patch up damaged areas in this way. “We should be able to get the brain to repair the damage itself rather than use a transplant,” Franklin pointed out.
For this, we need a better understanding of the cellular and molecular mechanisms of remyelination. There are two stages: recruitment of NSCs to the site of the injury, followed by the differentiation of the recruited cells into myelinating cells. “In MS, the cells get stuck and fail to differentiate into oligodendrocytes, which could repair the damage by producing myelin,” Franklin explained. He has therefore been looking at the two major pathways that play a role in this failure.
The well-known Wnt pathway inhibits NSC differentiation, and all the transcription factors involved have now been identified. One of these factors, Tcf4, looks like a significant player in MS. There is also a novel, lesser known pathway that induces NSC differentiation.
Franklin believes that small molecules might be able to drive these pathways toward differentiation and that candidates could come from oncology programs within pharma. Most colon cancers have a mutation within the Wnt pathway making it more active than it should be. “We do not need to start from ground zero in looking for a pharmacological approach to regenerative medicine; in MS we can move sideways,” Franklin commented. “We have become much more optimistic in the last 18 months.”
He added that human embryonic stem cells probably have more of a role in testing MS drugs compared to their therapeutic potential. “The U.K. is pretty much at the forefront in this,” according to Franklin. “Academia must now engage with industry, and this is starting to happen.”
Professor Gianvito Martino, director of the division of neuroscience at the San Raffaele Research Institute, Milan, described an immunomodulatory approach to MS using stem cells, which relies on the fact that stem cells produce many different substances that promote tissue homeostasis. “Instead of mere cell replacement, we should focus on these properties,” Martino asserted.
A key issue is which stem cells to use for this purpose. More than 400 MS patients worldwide have received autologous bone marrow cells with the aim of modulating or re-setting the immune system. But the mortality rate in trials is still 1–2%. As a consequence, hematopoietic stem cell therapy in MS can be considered, so far, only as rescue therapy for the most aggressive forms of the disease, Martino explained. Autologous mesenchymal stem cells are being tested in Phase I in the U.K., Israel, and Germany.
NSCs can be obtained from fetal, embryonic, and adult sources, and Martino believes the former is currently the most promising. The timing and administration route of these fetal NSCs is crucial. They express many immune system molecules and therefore migrate in a similar way to immune cells. “We can use these properties and inject the cells into blood or cerebrospinal fluid, and they will find their way to the MS lesion,” Martino stated. Then the NSCs seek out inflammatory cells, producing substances that kill the latter.
“Ten years ago the approach was to replace oligodendrocytes and repair damage,” Martino said. “Now the focus is upon changing the microenvironment around the damaged area and making the endogenous cells remyelinate through an NSC-mediated bystander, or paracrine, activity.”
Martino has been carrying out his work in mice and monkeys. “We now face the problem of getting enough material for human trials.” Scaling up might mean going to an academic center with a cGMP facility or maybe to a CMO. Martino emphasized that we don’t yet know what the ideal cell to transplant in MS will be or what the best delivery route will be. Nor is it known how best to obtain long-lasting integration of transplanted cells into the host tissue. Resolving these questions will be essential for the success of MS therapies based on stem cell transplantation.
Talking to GEN after the meeting, Professor Chris Mason, Advanced Centre for Biochemical Engineering, UCL, and co-founder of the LRMN, said that the Foundation’s funding model is a good one. Similar partnerships with, for instance, the Michael J. Fox Foundation, have been shown to work well. He is confident that promising projects will be funded promptly under the new agreement. “This whole area of MS has suddenly become very exciting. In particular, the immunomodulatory approach could be very powerful.