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FDA Approves First Clinical Trial of Stem Cells for ALS


doi: 10.1097/01.NT.0000365756.80192.71
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Investigators plan to use neuronal progenitor cells from fetuses around eight weeks old in the lumbar cords of ALS patients, with the hope that these cells will become motor neurons.

Every neurologist embarking on a new therapeutic trial knows what to expect when word gets out: phones ringing off the hook, from colleagues, patients, or their loved ones. Now throw in the term “stem cell therapy” and it raises the bar to even another level of great expectation and promise.



In early October, the FDA gave a nod to Neuralstem, Inc., a small biotechnology company in Rockville, MD, with one product on its shelf: a line of fetal neuronal cells that government regulators agree is ready to be tested in patients with amyotrophic lateral sclerosis (ALS).

Investigators will inject the human fetal stem cells into the lumbar spine of up to 18 ALS patients in what could be the first cellular therapy approach to the fetal neurodegenerative disease. The company is working with Jonathan Glass, MD, director of the Emory Neuromuscular Laboratory, and Eva Feldman, MD, PhD, director of the ALS Clinic at the University of Michigan, and their colleagues who have worked with neurosurgeon Nicholas Boulis, MD, to figure out how to safely deliver the cells into the spinal cord in humans. The scientists are now waiting for institutional review board approval from their institutions before they officially begin the study.

“This will be the first safety trial of stem cell injections for ALS in the United States,” said Dr. Glass.

Dr. Glass said that his phone has been ringing off the hook, with calls from patients or their loved ones willing to sign up.

The questions on the table are plentiful: Is it really possible to safely deliver cells into the spine without causing great harm on the way into and out of the cord? Will the cells do anything once they are there? What types of cells will they become and will that change if they were put somewhere else? And most important, will the cells lead to a clinical change for the better? “In reality, we just don't know,” he said. “That is precisely why we are doing this.”

Neurosurgeon Dr. Boulis has been working on the techniques necessary for safely injecting therapeutic agents into the human spinal cord, using a stereotactic frame to target delivery. Scientists knew that without the perfect delivery system there was no chance for any cell therapy for ALS. The spinal cord is a moving target and entry to and from can be dangerous. Nick the cord and a patient can become paralyzed. So Dr. Boulis worked on laboratory models, including pigs, until he figured out how to deliver the cells without damaging the spinal cord.



The investigators plan to use neuronal progenitor cells from fetuses around eight weeks old, with the hope that these cells will become motor neurons. Vassilis Koliatsos, MD, associate professor of pathology, neurology, neuroscience, and psychiatry at Johns Hopkins University, who has studied these cells, said that in theory, the cells can pump out growth factors and other cellular substances that could keep damaged motor neurons from dying or protect the ones that are still healthy.

Dr. Feldman, co-principal investigator of the study, is an expert on insulin-like growth factor-1 (IGF-1). Her work and others led to human trials of IGF-1 that ultimately provided no benefit to patients despite the promising animal data. About the fetal neuronal progenitor cells, she said in a University of Michigan news release: “In work with animals, these spinal cord stem cells both protected at-risk motor neurons and made connections to the neurons controlling muscles. We don't want to raise expectations unduly, but we believe these stem cells could produce similar results in patients with ALS.”

Lucie Bruijn, PhD, chief scientist at the ALS Association, said the study was “important because we are moving beyond the lab into humans. There has been a lot of preclinical work. Now, it's time to test these cells in patients.”

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But as many scientists have learned, “nothing in mice will predict what happens in humans,” said Jeffrey Rothstein, MD, a professor of neurology and neuroscience at Johns Hopkins University. Still, he countered his own skepticism by adding: “If we are ever going to do cellular therapy we have to start somewhere.”



He worries about the consistency of neuronal tissue from one patient to the next. Unlike a drug that has a specific effect that can be replicated on day one and decades later, the use of a fetal stem cell line may differ each time the cells turn over. “How many become astrocytes? How many neurons? Do we know how it behaves in one region and how it might work in another area? These cells are not clonal. In today's world, you would really like a well-defined cell.”

He said that Neuralstem's fetal neuronal cell has been around since 1999. The FDA has been very cautious about moving into human trials.

For now, no one is close to developing a motor neuron. There are scientists and companies working on developing lines of pure astrocytes that may serve to protect the motor neuron. And even if they had one in hand, studies suggest it could take as long as three years for an axon to find its way from a motor neuron in the spinal cord to a muscle in the human adult foot. “There are real challenges ahead of us,” Dr. Rothstein said.

Said Dr. Glass: ”We will move forward quickly, but always carefully.”

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• Yan J, Xu L, Koliatsos VE, et al. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Medicine 2007; 4(2):e39.
    • Xu L, Ryugo, Koliatsos VE, et al. Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: Differentiation and structural integration into the segmental motor circuitry. J Comp Neurol 2009; 514:297–309.
      • Yan J, Xu L, Koliatsos VE, et al. Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis transgenic mice. Stem Cells 2006; 24:1976 –1985.
        ©2009 American Academy of Neurology