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NIH Symposium: New Cellular Therapies Inch toward Clinical Utility, Investigators Report


doi: 10.1097/01.NT.0000333576.49974.a9

BETHESDA, MD—Just how far along is stem cell research? In an effort to answer that question, several leading investigators provided an overview of the field at a one-day research symposium hosted here by the NIH in May.

The take-home message, they said, in presentations on CNS disorders from multiple sclerosis (MS) to Parkinson disease (PD), is that stem cell research is inching closer to clinical application.

“There is no single stem cell type that is going to be adequate for all applications,” said NINDS Director Story C. Landis, PhD, who chairs the NIH Stem Cell Task Force. “I think the public wishes we were further along.” But she also noted that “if you read the lay press about stem cells, immediately it becomes polarized.”

Some Americans are outspokenly in favor of research on stem cell therapies to treat diseases such as PD and Alzheimer disease, she said, while others are adamantly opposed to this research for religious or moral reasons.

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Hematopoietic stem cell therapy (HST) is an established and effective approach to treating patients with nonmalignant and malignant blood disorders, and these applications have paved the way for using HST as an investigational therapy for MS and other autoimmune diseases, said Stuart H. Orkin, MD, a Howard Hughes Medical Institute Investigator at Children's Hospital Boston; the David G. Nathan Professor of Pediatrics at Harvard Medical School; and chair of the department of pediatric oncology at Dana-Farber Cancer Institute.

“Work of the past 25 years has defined the surface markers of HSCs (hematopoietic stem cells) and downstream progenitors that permit the prospective purification of cells for transplantation and biological study,” noted Dr. Orkin.

Mark S. Freedman, MD, professor of medicine (neurology) and director of the Multiple Sclerosis Clinic at the University of Ottawa, is studying the use of bone marrow-derived stem cells for MS in small numbers of carefully selected patients.

“We need to maximize patient selection to minimize toxicity; with high morbidity you can't give it to everyone,” noted Dr. Freedman, who has been investigating stem cell therapy in humans with MS for seven years. But, he said, “When you watch people get better it's very hard to ignore.”

Dr. Freedman told Neurology Today he has treated 18 patients and hopes to treat a total of 24. “The point of this whole line of therapy is, can you take a fixed deficit and repair it?” he noted. In those he has studied, “We have yet to see the disease restart,” he added.



Dr. Freedman presented preliminary results of these studies at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) last October in Prague. Future publications are in process, and Dr. Freedman is participating in a multicenter study funded by the Multiple Sclerosis Scientific Research Foundation, targeting multiple MS with intensive immunoablative therapy.

“The recipe for the successful treatment for MS probably entails curtailing the development and recurrence of inflammatory CNS attacks by the immune system but at the same time promoting the protection, repair, and ultimate regeneration of the damaged CNS elements,” explained Dr. Freedman. “This has led researchers to look at the possibility of combining a therapeutic approach that will both halt the autoimmune attack on the CNS — that is, immunosuppression — and provide a source of potential repair through the introduction of stem cells.”

Dr. Freedman said new studies “may be revealing that by completely staving off further CNS inflammatory attacks and by providing a healthy environment for the regrowth of the immune system, unfettered by continued disease-specific immunotherapy, there is a chance for CNS repair or regeneration in MS.”

Asked to comment on this research, in which she was not involved, Dr. Landis said, “MS is a special case,” and that Dr. Freedman and his collaborators “are actually treating an immune disorder.” She said there is evidence that if MS patients are carefully selected to avoid excess morbidity and mortality, stem cell therapy is probably safe, but to prove its efficacy in CNS repair this line of therapy would have to be studied in MS patients in a controlled phase 3 clinical trial.

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Douglas Kerr, MD, PhD, associate professor of neurology with a joint appointment in the department of molecular microbiology and immunology at Johns Hopkins University, is studying remyelination and motor neuron replacement in preclinical studies. At Johns Hopkins, he has established the Transverse Myelitis Center, the only one of its kind. “We've known stem cells can become any cell type, but we have not been able to control that process,” said Dr. Kerr.

He contends that the inherent characteristics of a specific type of stem cell, glial-restricted precursors (GRPs) — lineage-restricted precursors of CNS glial cells — “render them a natural means to repair defects in myelin production in the CNS, and thus may be an ideal therapy for CNS diseases such as transverse myelitis and MS.” Dr. Kerr and his team have previously shown that mouse embryonic stem cell-derived motor neurons injected into paralyzed rats with virus-damaged spinal cords can engineer new motor neuron circuits and restore partial functional movement in the hind limbs of the paralyzed animals.

Dr. Kerr said that he and other groups have found that GRPs hold promise for myelitis and MS, when these cells are transplanted into an inflammatory demyelinated lesion, rather than one from a chemical or genetic cause.



“GRPs do not fully differentiate and myelinate nearly as well as when transplanted into other types of demyelinated lesions.” Basically, he said, “When GRPs encounter the inflammatory environment seen in myelitis and MS patients, the differentiation of these cells halts, and they fail to repair myelin.” Thus, he said, the clinical potential of GRPs remains to be worked out in inflammatory preclinical models of demyelination.

“We are still considering how to deliver these cells in a multifocal way,” said Dr. Kerr. He said he hopes to begin clinical work with GRPs as early as 2009; he told Neurology Today the first trial will probably entail giving GRPs to about 15 carefully selected TM patients who are in the sub-acute phase of the disease. Dr. Kerr said the best time to give the GRPs will probably be between six weeks to one year post-diagnosis, when inflammation has abated and axons are still capable of myelination.

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Also in progress are efforts to combine stem cells and gene therapy for Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS), said Clive N. Svendsen, PhD, professor of neurology and anatomy at the University of Wisconsin-Madison; director of the NIH-funded Stem Cell Training Program; and co-director of the University of Wisconsin Stem Cell and Regenerative Medicine Center. Dr. Svendsen said human neuronal stem cells have been isolated from both embryonic stem cells and fetal brain tissue, and can be expanded in culture “without losing the potential to differentiate into both neurons and glia.”

Dr. Svendsen said a viable use of stem cells might be the replacement of damaged astrocytes and the delivery of large therapeutic proteins directly to the brain. He said that in animal models of PD and ALS, growth factors such as glial cell-derived neurotrophic factor (GDNF) have had neuroprotective effects. Dr. Svendsen noted that as stem cells migrate and integrate into the damaged CNS, they produce astrocytes and can be genetically modified to release a neuroprotective growth factor. Thus “they are an ideal source of tissue for delivery,” he said.

A possible clinical strategy to slow death from a neurological disease might combine the “inherent trophic effects of glia derived from stem cells” with selective gene therapy, he said. “The idea in patients would be to replace the neurons that are sick with human neuronal cells that release GDNF,” said Dr. Svendsen. He noted that human trials await the availability of regulated vectors to allow the appropriate dosing of GDNF. He said he is now working on a clinical protocol that involves delivery of neural cells into the spinal cord. “GDNF cannot be given as a pill because it will not enter the brain,” he noted.

Asked to comment on Dr. Kerr's and Dr. Svendsen's preclinical research, Dr. Landis said the presentations are about “early work,” and “the questions they're asking are much more difficult” than those being asked in use of stem cell therapy for MS. “They're talking about replacing brain cells,” she said. “They've set the bar much higher.”

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In presentations on CNS disorders from multiple sclerosis (MS) to Parkinson disease (PD), investigators provided an overview of advances in stem cell research.

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• Freedman MS, Atkins HL, Bar-OR, et al., on behalf of the Canadian BMT Study Group. Immune ablation and autologous stem cell transplantation for aggressive multiple sclerosis: Interim 5-year report. 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Abstract 73. Oct. 13, 2007.
    • Freedman MS, Atkins HL. Suppressing immunity in advancing MS: Too much too late, or too late for much? Neurology 2004;62:168–169.
      • Maragakis NJ, Rao MS, Rothstein JD, et al. Glial restricted precursors protect against chronic glutamate neurotoxicity of motor neurons in vitro. Glia 2005;50(2):145–159.
        • Suzuki M, Svendsen CN. Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis. Trends Neurosci 2008;31(4):192–198.
          • Suzuki M, McHugh J, Svendsen CN, et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS One 2007;2(1):e689.
            • Klein SM, Behrstock S, Svendsen CN, et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther 2005;16(4):509–521.
              ©2008 American Academy of Neurology