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News from Newscientisttech.com
Stem cell genes may provide
medicine's dream ticket
GENE therapy meets stem cells. That is the wave of the future, if
the recent annual meeting of the American Society of Gene Therapy in
Seattle is any guide. There was a palpable buzz around efforts to
correct diseases by targeting therapeutic genes to stem cells
already resident in the body.
Clinical trials are on the horizon for treatments for diabetes and a
group of fatal neurodegenerative conditions called lysosomal
storage diseases. Meanwhile, gene therapists are also using
their skills to make "improved" stem cells for regenerative
therapies (see "Stem cell enhancement"). "If you look at what is
happening today and what is in the pipeline, I think genetic
modification of stem cells is going to be a major theme," says Luigi
Naldini of the San Raffaele Telethon Institute of Gene Therapy in
Milan, Italy.
Stem cells have obvious appeal as targets for gene therapy, in which
genes are inserted into an individual's cells in order to treat a
disease. Once modified to carry a therapeutic gene, stem cells
should continue to divide as normal, replenishing themselves and
producing specialised daughter cells that will carry the same gene.
By contrast, most other cells have a limited lifespan and capacity
for division - one reason why gene therapists have so far struggled
to achieve effective and lasting treatments.
Indeed, the most conspicuous success of gene therapy to date - the
treatment of children with a severe inherited immune deficiency -
was achieved by correcting genetic defects in blood-forming stem
cells in their bone marrow. Now gene therapists are focusing on
other types of stem cells and different diseases.
Among the most promising examples in Seattle was a therapy for type
1 diabetes based on modifying stem cells in the gut. People with
type 1 diabetes are unable to regulate their blood sugar because
their immune system destroys beta cells in the pancreas, which
secrete insulin. The disease can be treated with insulin injections,
but it is hard to mimic the body's precise regulation of insulin
levels in response to glucose.
What's needed, says Anthony Cheung of enGene, a biotech company in
Vancouver, Canada, is a type of cell that is sensitive to glucose
and which can be engineered to produce insulin. K cells, which are
found in the upper part of the small intestine, are good candidates
as they produce a hormone called GIP in response to glucose in the
gut. GIP sends a message to the pancreas that food is coming,
priming the production of insulin. If K cells could be engineered to
produce insulin themselves, they would cut out the middleman and
deliver the hormone when it is needed.
The problem is that individual K cells live for only about a week
before they are sloughed off into the gut. So enGene needed to
deliver the gene for insulin to the stem cells that continually give
rise to new K cells.
The company has now cracked this, using nanoparticles of a
polysaccharide called chitosan, found in shrimp shells, to deliver
the genes to the cells. The nanoparticles carry two loops of DNA
called plasmids, one bearing the gene for human insulin, the other
encoding an enzyme that can insert the insulin gene into a cell's
genome. After a single dose of nanoparticles, animals produced human
insulin for more than 130 days. "We're looking to move this into
clinical trials by early 2009," says Cheung.
"After a single dose of nanoparticles, animals produced human
insulin for more than 130 days"
Because some stem cells are only accessible for modification during
a narrow window of embryological development, a few groups are
experimenting with in utero gene therapy to correct inherited
diseases such as some forms of breast cancer. Jesse Vrecenak and her
colleagues at the Children's Hospital of Philadelphia in
Pennsylvania have modified the stem cells that form breast tissue by
injecting lentiviruses that carry a marker gene into the amniotic
fluid of pregnant mice. Eventually, this may enable carriers of the
breast cancer genes BRCA1 and BRCA2 to bear children with healthy
copies of the genes in their breast tissue.
Meanwhile, other researchers are working on ways to extract stem
cells from the body, genetically modify them in the lab, and then
return them to exert a therapeutic effect.
At the San Raffaele Telethon Institute, Alessandra Biffi and her
colleagues are planning a clinical trial using modified bone marrow
stem cells to treat metachromic leukodystrophy, or MLD. This is a
lysosomal storage disease (LSD) in which toxins called sulphatides
build up in the brain, and nerves lose their insulating layer of
myelin. Children with severe forms of MLD go into a steep cognitive
decline and lose motor control, usually dying before the age of 10.
The disease is caused by defects in the gene for an enzyme called
ARSA. In experiments on mice, Biffi's team has shown that stem cells
from the bone marrow can be modified to boost the production of ARSA
and correct MLD. The stem cells give rise to immune cells called
microglia, which migrate to the brain. "You can really generate a
shuttle for your enzyme into the nervous system," Biffi says. Early
next year, she will begin recruiting children with severe MLD into a
clinical trial of the therapy.
Biffi's colleague Angela Gritti is also concentrating on LSDs, but
she is adding genes for therapeutic enzymes to neural stem cells,
which can give rise to new brain tissue. For some LSDs, Gritti
believes they may need to modify both blood-forming and neural stem
cells. "We also need a high degree of tissue repair," she says.
Neural stem cells also have some subtler therapeutic effects. Evan
Snyder's team at the Burnham Institute for Medical Research in La
Jolla, California, has delayed the onset of symptoms in a mouse
model of an LSD called Sandhoff disease by injecting healthy human
neural stem cells into the mice's brains. As well as providing the
missing enzyme, the stem cells also had an anti-inflammatory effect,
further protecting the brain.
While the idea of using stem cells to rebuild diseased tissues grabs
most attention, Snyder predicts that their ability to deliver
corrective genes and to protect other cells from damage will have a
bigger impact in the future. "The low-hanging fruit are these
molecular therapies," he says.
From issue 2608 of New Scientist magazine, 13 June 2007, page 14-15
Stem cell enhancement
"People are excited about the potential of stem cells, but most
approaches are not leveraging them to their maximum potential," says
Madhusudan Peshwa of MaxCyte in Gaithersburg, Maryland. "We're not
getting into the driving seat and getting the cells to do what we
want them to do."
Many teams have attempted to use adult stem cells in regenerative
medicine - to repair damaged tissue after a heart attack, for
example -but their efforts have been hampered by problems such as
cells dying before reaching their target or not differentiating into
the correct cell type.
Now researchers are waking up to the idea of genetically modifying
stem cells to enhance their natural attributes and gain a new level
of control over them. In the case of heart attacks, stem cells from
both skeletal muscle and bone marrow have been shown to repair
tissue damage to some degree, either through differentiating into
heart muscle cells or releasing chemicals that stimulate existing
cells to repair the damage. To make this process more effective,
Marc Penn at the Center for Stem Cell and Regenerative Medicine in
Cleveland, Ohio, genetically engineered bone marrow stem cells to
produce triple the normal amount of a signalling factor called
SDF-1. This is an "SOS signal" also released by damaged heart cells
after an attack and is thought to recruit repair cells to the
damaged area.
"The idea is to try and restart natural signals that initiate repair,"
says Penn. When the cells were injected into rats' hearts after a
heart attack, the team saw a 70 per cent reduction in heart cell
death, compared with rats given unmodified stem cells (The FASEB
Journal, DOI: 10.1096/fj.06-6558com).
Meanwhile, Duncan Stewart at the University of Toronto, Canada, is
focusing on a more differentiated group of cells called endothelial
progenitor cells (EPCs), to develop a therapy for pulmonary arterial
hypertension (PAH). This is a fatal condition in which tiny blood
vessels carrying blood to the lungs are destroyed. Previous studies
have shown that EPCs can protect blood vessels against future damage,
but Stewart's team wanted EPCs to repair damage to blood vessels
after it had occurred.
Endothelial cells usually produce an enzyme called eNOS, which is
thought to promote blood vessel growth and protect against cell
death. Stewart's team inserted a circular piece of DNA containing
the gene for eNOS into EPCs, and then injected the cells into rats
with damaged lung vessels. The rats showed a significant improvement
in blood flow to the lungs and more survived compared with untreated
rats.
"EPCs by themselves seem to have some effect, but you can get much
better effects if you push the cells in the right direction," says
Stewart, who presented his results at Bio2007 in Boston last month.
He has now begun a safety study of eNOS-modified EPCs in 18 humans
with PAH.
Linda Geddes
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