Genetically Modified Cells Migrate to Brain and Treat
Neurodegeneration
Physicians might one day be able to treat a disease that destroys
brain cells in children using genetically modified cells to transport
a "drug" to the site of the dying neural cells (cells that transmit
impulses).
This discovery occurred based on results of a laboratory study of the
technique published by investigators at St. Jude Children's Research
Hospital. A report on this work appears in the prepublication online
issue of Blood.
There is currently no cure for such disorders, which are called
lysosomal storage diseases (LSDs).
The St. Jude researchers successfully treated a laboratory model of
an LSD called GM1 - gangliosidosis using bone marrow cells (BMCs)
into which scientists inserted the gene for an enzyme that breaks
down a fat molecule called GM1.
GM1 is a critical component of normal brain cells. But in GM1 -
gangliosidosis, brain cells lack this enzyme-beta-
GM1 accumulates to such a high concentration that it disrupts the
proper function of the cell and causes it to self-destruct.
BMCs include a population of so- called pluripotent stem cells-cells
that give rise to a variety of different cell types that have
specific functions, such as the immune cells called monocytes.
After the St. Jude team infused the genetically modified BMCs into
the laboratory model, resulting monocytes migrated to the
degenerating brain cells that lacked the gene for beta-galactosidase.
These cells took in the enzyme released by the monocytes and used it
to break down excess GM1, thus correcting the potentially fatal
buildup of this molecule.
The monocytes homed in on the brain by following a trail of signaling
molecules that were released by cells adjacent to the degenerating
neurons, according to Alessandra d'Azzo, Ph.D., a member of the St.
Jude department of Genetics and Tumor Cell Biology. Such signaling
proteins are called chemokines.
Under a disease condition, these brain cells, called astrocytes and
microglia, release chemokines in order to trigger a migration of
immune cells to areas of the brain that are damaged. d'Azzo is senior
author of the article in Blood.
"We used the brain's own signaling molecules to guide the genetically
modified monocytes along a concentration gradient to the degenerating
brain cells," d'Azzo said. A gradient is a pathway of increasing
concentration of a specific substance.
In the St. Jude study, the BMCs followed the gradient toward
increasing concentrations of the chemokines until they reached the
site of the degenerating neurons.
Normally, the immune cells recruited to the brain by chemokines would
cause inflammation and worsen the damage. But in this case, the
genetically modified monocytes restored the beta-galactosidase
activity, which in turn decreased the extent of neuron degeneration
and chemokine levels.
"We showed that improvement of the disease was directly related to
the amount of genetically modified monocytes reaching the
degenerating brain cells," said Renata Sano, Ph.D., a researcher in
St. Jude Genetics and Tumor Cell Biology and the paper's first
author. "The improvement was clearly linked to the ability of the
corrected neurons to break down excess GM1 with the enzyme delivered
by the monocytes. Overall, our findings suggest that if this
technique could be adapted to treat children with this type of LSD we
would have an effective therapy."
Key to the promise of curing LSDs in children using this technique is
the fact that since BMCs are stem cells, they continually give rise
to all the various types of blood cells in the body, including
monocytes, d'Azzo said.
Therefore, genetically modified BMCs would be able to produce an
endless supply of monocytes carrying the gene for beta-galactosidase,
ensuring that the enzyme would always be available to affected
neurons in the brain of children with GM1 - gangliosidosis.
If the BMCs were harvested from the same child who is treated with
them after these cells are genetically modified, this would eliminate
the potential complications arising from transplanting BMCs from a
donor.
d'Azzo previously showed that GM1 - gangliosidosis is an inherited
disease in which one of the enzymes in the lysosomes is defective
(Molecular Cell, Sept. 10, 2004; http://www.stjude.
Lysosomes are the cell's recycling centers, where proteins, fats and
other molecules are broken down into their basic building blocks,
which are then reused to make new molecules. LSDs occur when
lysosomes lack the enzymes they need to perform their recycling
tasks, leading to abnormal accumulation of the molecules the lysosome
is supposed to break down.
These diseases, including GM1 - gangliosidosis, are responsible for
most severe cases of neurodegeneration and mental retardation among
children.
The other authors of this paper include Alessandra Tessitore
(currently at Telethon Institute of Genetics and Medicine; Naples,
Italy) and Angela Ingrassia (St. Jude).
This work was supported in part by the National Institutes of Health,
a Cancer Center Support Grant, the Assisi Foundation of Memphis and
ALSAC. d'Azzo holds the Chair in Genetics and Gene Therapy endowed by
the Jewelers Fund for Children.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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