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Is the Science of Stem Cells Ready?

VBCN - May 2015 Volume 2, No 1 - Clinical Trials
Chase Doyle

Washington, DC––At the 2015 annual meeting of the American Academy of Neurology, experts engaged in a series of debates that touched on current and controversial issues in the field of neuroscience. During a debate on the role of stem-cell science in neurologic diseases, Clive Svendsen, PhD, Director of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, argued that based on recent advances in technology, including induced pluripotent stem cells (iPSCs), the science of stem cells is ready for clinical trials in neurologic disease. Conversely, C. Warren Olanow, MD, FRCPC, Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology, Professor of Neuroscience, Mount Sinai School of Medicine, New York, insisted that more supportive evidence is needed in this field before stem cells are introduced into neurologic clinical trials.

Turning Lead into Gold


The recent Nobel Prize–winning discovery that adult skin cells can be taken from patients and reprogrammed into a pluripotent state almost identical to embryonic stem cells sent shockwaves through the scientific world, and Dr Svendsen was unequivocal with regard to iPSCs’ transformative potential.

“This is a very important technology,” he said. “We can make these stem cells from patients with Parkinson’s disease or ALS [amyotrophic lateral sclerosis] or other neurologic disorders and learn about the disease mechanisms… It’s like turning lead into gold.”

Based on Dr Svendsen’s assertion, iPSC science may eventually provide an ethically acceptable, potentially autologous source of neural cells for transplantation in patients with neurologic diseases. However, the scientific challenges facing transplantation into patients with Parkinson’s disease are substantial.

“If you put the cells back where they died, they can’t reconnect,” said Dr Svendsen. “Parkinson’s is more than just the loss of dopamine neurons. We have to face the challenge of other parts of the nervous system regenerating. But, if we can attack the dopamine system, it will be very beneficial for Parkinson’s disease.” He further added, “Embryonic stem cells can make neurons, but it’s very hard work to get these cells to integrate.”

Despite these challenges, Dr Svendsen believes that the science of creating dopamine neurons from stem cells is ready to move to the clinic again. Gene editing to regulate dopamine release, suicide gene insertion, and improved control over the numbers and the quality of cells are just a few of the new strategies highlighted by Dr Svendsen.

“Oligodendrocytes may be even more practical,” he suggested, “and remyelinating clinical trials for MS [multiple sclerosis] are currently being developed using stem-cell technology. Oligodendrocytes could also be used for spinal cord injury.”

Dr Svendsen also discussed astrocytes, which may be dysfunctional in many neurologic diseases. Stem cells can generate new astrocytes following transplantation, Dr Svendsen said, which could be used to deliver drugs that prevent cell death and enhance plasticity.

“Replacing sick astrocytes with healthy astrocytes that secrete GDNF [glial cell-derived neurotrophic factor] in ALS may limit the progression of motor neuron degeneration,” he hypothesized. “Overall, the science is clearly ready.”

Not Ready for Prime Time

Dr Olanow countered Dr Svendsen’s position with a compelling statistic—the failure of every single double-blind clinical trial to date involving cell transplantation.

“We failed in our trial despite the fact that fetal nigral cells demonstrated robust survival with hundreds of thousands of implanted neurons and extensive striatal innervation,” said Dr Olanow. “This contrasts with stem cells, which do not show the same level of survival or the same level of striatal innervation.”

Transplanted fetal nigral cells also showed robust motor benefits in animal models, Dr Olanow emphasized, but still failed in a double-blind clinical trial in patients with Parkinson’s disease.

“Why would we believe stem cells would do better when they have less reinnervation, less cell survival, and less clinical benefit?” Dr Olanow asked Dr Svendsen. The science is not only unlikely to succeed but also comes with debilitating risk, Dr Olanow said. Dopamine transplant studies were associated with the development of unanticipated graft-induced dyskinesia in as many as 50% of patients.

“This dyskinesia can be severe and requires deep brain stimulation, a source of tremendous disability for the patient,” Dr Olanow explained. “Why would stem cells obviate this risk?”

Finally, Dr Olanow argued that even if stem-cell transplantation were to succeed, its advantage over currently available and future therapies that treat and even prevent motor complications would be negligible.

“I’m an experimental therapist. My argument is not that we shouldn’t keep going, but that we need to think about it before we do. More science is needed before we are ready to step forward into the clinic, given what we know now,” concluded Dr Olanow.

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