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Neurology Today:
doi: 10.1097/01.NT.0000426341.23384.4a
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Neural Stem Cells Reach Gliomas Intranasally

Collins, Thomas R.

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Researchers have shown that applying neural stem/progenitor cells (NSPCs) intranasally is an effective way to target gliomas in the brain of a mouse model, according to a study published in the Nov. 26, 2012, online edition of the journal Stem Cells Translational Medicine.

The findings represent another step forward in the understanding of how NSPCs might be used to deliver stem cell-based therapies that can cross the blood-brainbarrier in a non-invasive way.

Researchers — led byprincipal investigator Nils Ole Schmidt, MD, of the department ofneurosurgery at the University Medical Center Hamburg-Eppendorf in Hamburg, Germany — said that the same signals likely responsible for attracting the NSPCs to the tumors might also be effective in other neurological disorders like stroke and brain trauma. Dr. Schmidt collaborated with researchers from University College Medicine in Seoul, Korea, and from the University of British Columbia Hospital in Vancouver.

“Intranasally-administered NSPCs displayed a rapid, targeted tumor tropism with significant numbers of NSPCs accumulating specifically at the intracerebral glioma site within 6 hours after intranasal delivery,” researchers wrote in the study.

The cells reached tumors mainly through the olfactory nerve, which originates in the brain and extends nerve endings through the lamina cribosa to the nasal cavity. To some extent the NSPCs also traveled through the microvasculature of the nasal mucosa. This is consistent with previous findings on how the technique gets around the blood-brain barrier.

Mice were injected with human glioblastoma cells, and then 10 days later the NSPCs were administered intranasally. Within six hours, the cells appeared at the tumor sites at a density of 32 per square millimeter within the tumor and 27 per square millimeter around the tumor. After 24 hours, the density increased to 51 cells per square millimeter within the tumor and 47 cells per square millimeter around the tumor.

In all, 43,210 NSPCs were found in the defined tumor area, showing that 14.4 percent of the cells made it to the target.

No NSPCs were seen in the control mice that didn't have glioma injected. Dr. Schmidt said they likely getswallowed or released by the mucosa or just die.

He said there is some evidence that the stem cells themselves have some kind of therapeutic value, but they would mainly be used as vehicles to deliver a prodrug-converting enzyme produced by the cells to create achemotherapy that is toxic to tumors. Dr. Schmidt also said they might be able to be used to produce apoptosis-inducing molecules and molecules that modulate the immune response.

Dr. Schmidt sees the role of NSPCs as potentially far-reaching in the treatment of neurological disorders.

Vascular endothelial growth factor (VEGF) has been shown previously to guide and attract cells from distant parts of the brain, Dr. Schmidt said, referring to a 2005 report in Neoplasia. VEGF is likely the guiding force here in drawing the NSPCs to the tumor, Dr. Schmidt said.

“It seems likely that this is one of the major factors attracting NSPCs,” he told Neurology Today. “Interestingly, VEGF is not only released in the context of brain tumors but in many other neurological disorders such as stroke and trauma. Targeted NSPC migration is not tumor-specific. It is rather that the cells have some kind of intrinsic capacity to ‘detect’ pathological areas within the brain. The cells do also migrate towards stroke areas, traumatized brain, or spinal cord tissue.”

William Frey II, PhD — director of the Alzheimer's Research Center at Regions Hospital in St. Paul, MN, whose research laid the groundwork for the intranasal application method of stem cells to the brain in a 2009 paper in the European Journal of Cell Biology, and who now holds a patent for the technique along with co-researchers — said the findings are “a major breakthrough that opens the door to regenerative medicine treatments for central nervous system disorders.”

“This intranasal delivery, targeting and treatment technology can make stem cell treatments practical for CNS disorders by eliminating the need for invasive neurosurgical implantation of cells and by eliminating the need for intravenous delivery that disperses cells throughout the body resulting in unwanted systemic exposure,” he said.

Alfredo Quinones-Hinojosa, MD, director of the Brain Tumor Surgery Program at Johns Hopkins Bayview Medical Center, said this is the kind of research that might allow therapy for brain tumors to jump to the next level.

“We are at a stage in science where we can effectively attack brain tumors in vitro but are failing in delivering these therapies selectively in vivo,” he said.

He pointed out potential obstacles for use in humans, though. “There is a long way to go in order to successfully implement a method like this in human patients, nevertheless it's encouraging to see its effectiveness in mice,” he said. “One thing to keep in mind is that the rodent olfactory system is very different and larger as compared to the human olfactory system and this may present a challenge when trying to use similar methods in the human brain.”

Dr. Schmidt acknowledged this anatomy challenge, but remained optimistic.

Dr. Quinones-Hinojosa also said the delivery needs to be honed for the greatest effect. “The actual procedure needs to be optimized to get the maximum number of cells to travel to the tumors and yet make it as safe as possible for patients,” he said. “The paper shows there is effective homing of the stem cells to tumors, but this is still lower than optimal.”

Dr. Schmidt said the team has already started down this road, testing NSPCs that deliver different therapeutic payloads and gauging therapeutic efficacy when the cells are delivered as nose drops. They're also comparing nasal administration with other applications and trying to establish dose-response relationships in their mouse brain tumor model, he said.

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FOR FURTHER READING:

• Reitz M, Demestre M, Schmidt NO, et al. Intranasal delivery of neural stem/progenitor cells: A non-invasive passage to target intracerebral glioma. Stem Cells Transl Med 2012; E-pub 2012 Nov. 26.
• Schmidt NO, Przylecki W, Yang W, et al. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 2005;7:623–629.
• Danielyan L, Schafer R, von Ameln-Mayerhofer A, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol 2009;88:315–324.

©2013 American Academy of Neurology

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