barbara
09-19-2010, 10:30 PM
This article is a year old, but what an interesting idea.
Neurology Today:
3 August 2009 - Volume 9 - Issue 15 - pp 1,11-13
doi: 10.1097/01.NT.0000360212.46369.3f
Intranasal Delivery of Stem Cells Bypasses Blood-Brain Barrier
TALAN, JAMIE
ARTICLE IN BRIEF A new technique for delivering stem cells - intranasally - could be less toxic and helpful for other CNS therapies, investigators report.
A team of scientists has discovered that stem cells delivered intranasally can bypass the blood-brain barrier and make their way into the brain. The technique could possibly be useful for delivering other therapies directly into the brain and avoid the systemic effects that can arise when medicines circulate through the bloodstream, according to the investigators whose report appears in the June issue of the European Journal of Cell Biology.William H. Frey, II, PhD, director of the Alzheimer's Center at Regions Hospital and professor of pharmaceutics, neurology, and neuroscience at the University of Minnesota in St. Paul, has been testing non-invasive intranasal delivery of pharmaceuticals for two decades. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways, Dr. Frey explained. He added that delivery occurs by an extracellular route and does not require that the drugs bind to any receptor or undergo axonal transport.
Dr. Frey had been looking for safe ways to get molecules into the brain, especially large ones like insulin and nerve growth factor, many of which can't breach the blood-brain barrier. He tagged the medicines so he could define their route and soon discovered that they travelled along the olfactory nerves involved in smell and the trigeminal nerves involved in pain. Within minutes the medicine introduced into the nose made its way into the brain without even entering the bloodstream appreciably for many drugs.His foray into the intranasal delivery of CNS therapeutics began with therapeutic proteins such as insulin. Other researchers have suggested that Alzheimer disease (AD) is akin to diabetes of the brain. Glucose uptake and utilization is low, as shown on PET, in part because insulin is low in the brains of patients with AD. These patients do not regulate glucose properly in the brain, and Dr. Frey and others believed that was one reason why the brain had problems remembering.
INTRANASAL INSULIN
Last year, Suzanne Craft, PhD, and colleagues at the University of Washington reported in Neurology that intranasal insulin improved attention, memory, and cognition and also modulated beta-amyloid in patients with early AD who had received two daily doses of intranasal insulin for 21 days. The improvement is not likely to be just symptomatic, Dr. Frey explained. The brain recognizes a rush of insulin and reduces this signal by producing insulin degrading enzyme, and that in turn helps get rid of amyloid.The success with these large molecules led Dr. Frey to experiment with delivering genetically-engineered cells. He teamed up with Lusine Danielyan, PhD, of University Hospital of Tuebingen in Germany, who had similar ideas. They designed a study to deliver bone marrow-derived stem cells from rats and human glioma cells intranasally to na?ve rats and mice.The cells were stained with fluorescent dye so that they could easily be tracked. In another series of studies they treated the nasal mucosa with a naturally occurring enzyme called hyaluronidase that is known to degrade the extracellular matrix between cells and also helps sperm penetrate eggs. They thought this might help the stem cells migrate better into the brain.In both cases, the stem cells reached the brain within one hour. When hyaluronidase was used, twice the number of stem cells made it into the brain.We see these stem cells in the olfactory bulb, thalamus, hippocampus, and in the cortex, Dr. Frey explained. The stem cells crossed the olfactory epithelium at the roof of the nasal cavity and went through the part of the skull that separates the nasal cavity from the brain (the cribriform plate). There are little holes in the cribriform plate through which the olfactory nerve bundles and signals travel from the nose into the brain. Blood vessels also feed the nerves, and they have evidence that the cells travel through the perivascular space and are possibly propelled into the brain by the pulsing movement of the blood.The experiments conducted by Dr. Danielyan and our colleagues show that it is possible without surgery to deliver stem cells to the brain, Dr. Frey said. This could revolutionize regenerative medicine. Any type of cell can be delivered with this approach.Next, he will study the efficacy of intranasal cell therapy in an animal model of a neurological disease.This is quite an innovative approach, said Patricio Reyes, MD, director of the Alzheimer's Disease and Cognitive Disorders Program of the Barrow Neurological Institute in Phoenix, AZ. More that two decades ago Dr. Reyes demonstrated that the olfactory system has the highest density of amyloid plaque in patients with AD and that many patients lose their ability to smell and taste.In collaboration with Dr. Frey, Dr. Reyes said that he is now designing studies to test the benefits of intranasal delivery of medications to the brain for treating AD, Parkinson disease, and gliomas. This opens up a whole new pathway for drug delivery, Dr. Reyes said. The agents that are being delivered don't have to circulate systemically and potentially damage organ systems. We could direct our therapy.The caveat: We don't know the potential risks yet. Hopefully we will be able to understand the various methods and the safest way to deliver compounds, said Dr. Reyes.Sally Temple, PhD, scientific director of the New York Neural Stem Cell Institute in Rensselaer, NY, said that it is a great idea to explore other cell delivery methods, and this is certainly out of the box. It will take more analysis to see if cells enter the brain this way in significant numbers. We need to be sure that the labeled items are truly live donor cells, and not fluorescent debris that has been taken up into phagocytic cells, or cells fused with other cells, which can happen.What's more, she added, Dr. Frey and his colleagues, or others, need to show that the donor cells have entered the brain tissue and are not trapped in vessels or within the linings of the brain. I like that they are moving towards using genetically labeled cells which is better than using dyes, and if they show high power images it will provide more critical evidence to support this novel approach.
References
Danielyan L, Sch?fer R, Frey WH, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol 2009;88(6):315-324. E-pub 2009 Mar 25.
Reger MA, Watso GS, Craft S, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70: 440-448.
View Full Text | PubMed | CrossRef
Neurology Today:
3 August 2009 - Volume 9 - Issue 15 - pp 1,11-13
doi: 10.1097/01.NT.0000360212.46369.3f
Intranasal Delivery of Stem Cells Bypasses Blood-Brain Barrier
TALAN, JAMIE
ARTICLE IN BRIEF A new technique for delivering stem cells - intranasally - could be less toxic and helpful for other CNS therapies, investigators report.
A team of scientists has discovered that stem cells delivered intranasally can bypass the blood-brain barrier and make their way into the brain. The technique could possibly be useful for delivering other therapies directly into the brain and avoid the systemic effects that can arise when medicines circulate through the bloodstream, according to the investigators whose report appears in the June issue of the European Journal of Cell Biology.William H. Frey, II, PhD, director of the Alzheimer's Center at Regions Hospital and professor of pharmaceutics, neurology, and neuroscience at the University of Minnesota in St. Paul, has been testing non-invasive intranasal delivery of pharmaceuticals for two decades. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways, Dr. Frey explained. He added that delivery occurs by an extracellular route and does not require that the drugs bind to any receptor or undergo axonal transport.
Dr. Frey had been looking for safe ways to get molecules into the brain, especially large ones like insulin and nerve growth factor, many of which can't breach the blood-brain barrier. He tagged the medicines so he could define their route and soon discovered that they travelled along the olfactory nerves involved in smell and the trigeminal nerves involved in pain. Within minutes the medicine introduced into the nose made its way into the brain without even entering the bloodstream appreciably for many drugs.His foray into the intranasal delivery of CNS therapeutics began with therapeutic proteins such as insulin. Other researchers have suggested that Alzheimer disease (AD) is akin to diabetes of the brain. Glucose uptake and utilization is low, as shown on PET, in part because insulin is low in the brains of patients with AD. These patients do not regulate glucose properly in the brain, and Dr. Frey and others believed that was one reason why the brain had problems remembering.
INTRANASAL INSULIN
Last year, Suzanne Craft, PhD, and colleagues at the University of Washington reported in Neurology that intranasal insulin improved attention, memory, and cognition and also modulated beta-amyloid in patients with early AD who had received two daily doses of intranasal insulin for 21 days. The improvement is not likely to be just symptomatic, Dr. Frey explained. The brain recognizes a rush of insulin and reduces this signal by producing insulin degrading enzyme, and that in turn helps get rid of amyloid.The success with these large molecules led Dr. Frey to experiment with delivering genetically-engineered cells. He teamed up with Lusine Danielyan, PhD, of University Hospital of Tuebingen in Germany, who had similar ideas. They designed a study to deliver bone marrow-derived stem cells from rats and human glioma cells intranasally to na?ve rats and mice.The cells were stained with fluorescent dye so that they could easily be tracked. In another series of studies they treated the nasal mucosa with a naturally occurring enzyme called hyaluronidase that is known to degrade the extracellular matrix between cells and also helps sperm penetrate eggs. They thought this might help the stem cells migrate better into the brain.In both cases, the stem cells reached the brain within one hour. When hyaluronidase was used, twice the number of stem cells made it into the brain.We see these stem cells in the olfactory bulb, thalamus, hippocampus, and in the cortex, Dr. Frey explained. The stem cells crossed the olfactory epithelium at the roof of the nasal cavity and went through the part of the skull that separates the nasal cavity from the brain (the cribriform plate). There are little holes in the cribriform plate through which the olfactory nerve bundles and signals travel from the nose into the brain. Blood vessels also feed the nerves, and they have evidence that the cells travel through the perivascular space and are possibly propelled into the brain by the pulsing movement of the blood.The experiments conducted by Dr. Danielyan and our colleagues show that it is possible without surgery to deliver stem cells to the brain, Dr. Frey said. This could revolutionize regenerative medicine. Any type of cell can be delivered with this approach.Next, he will study the efficacy of intranasal cell therapy in an animal model of a neurological disease.This is quite an innovative approach, said Patricio Reyes, MD, director of the Alzheimer's Disease and Cognitive Disorders Program of the Barrow Neurological Institute in Phoenix, AZ. More that two decades ago Dr. Reyes demonstrated that the olfactory system has the highest density of amyloid plaque in patients with AD and that many patients lose their ability to smell and taste.In collaboration with Dr. Frey, Dr. Reyes said that he is now designing studies to test the benefits of intranasal delivery of medications to the brain for treating AD, Parkinson disease, and gliomas. This opens up a whole new pathway for drug delivery, Dr. Reyes said. The agents that are being delivered don't have to circulate systemically and potentially damage organ systems. We could direct our therapy.The caveat: We don't know the potential risks yet. Hopefully we will be able to understand the various methods and the safest way to deliver compounds, said Dr. Reyes.Sally Temple, PhD, scientific director of the New York Neural Stem Cell Institute in Rensselaer, NY, said that it is a great idea to explore other cell delivery methods, and this is certainly out of the box. It will take more analysis to see if cells enter the brain this way in significant numbers. We need to be sure that the labeled items are truly live donor cells, and not fluorescent debris that has been taken up into phagocytic cells, or cells fused with other cells, which can happen.What's more, she added, Dr. Frey and his colleagues, or others, need to show that the donor cells have entered the brain tissue and are not trapped in vessels or within the linings of the brain. I like that they are moving towards using genetically labeled cells which is better than using dyes, and if they show high power images it will provide more critical evidence to support this novel approach.
References
Danielyan L, Sch?fer R, Frey WH, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol 2009;88(6):315-324. E-pub 2009 Mar 25.
Reger MA, Watso GS, Craft S, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70: 440-448.
View Full Text | PubMed | CrossRef