- A California biotech company has a technology that seems
like a killer application for gene therapy: It can turn any gene on or
off.
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- In some ways it really is a killer app. The technology
allows a scientist to genetically engineer a protein with what is called
a zinc finger. Heart not pumping hard enough for lack of good blood vessels?
Turn on the blood vessel-growing gene. Want to stop a patient from getting
fatter? Turn off the gene that makes fat cells.
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- But biology is not yet up to speed with zinc finger technology.
First, researchers have to identify which genes are associated with which
diseases so they know what they're turning on or off. Until then, there
will be a limit on what zinc fingers can do.
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- Still, Sangamo BioSciences, the home of zinc finger technology,
says zinc fingers will lead to breakthrough therapies for any disease that
relies on a gene's activity.
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- "Once that biology is done ... Sangamo will be the
beneficiary," said Ed Lanphier, president and CEO of http://www.sangamo.com
Sangamo.
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- Zinc fingers occur naturally inside the nucleus of all
organisms, where they bind to DNA to turn genes on or off. They are the
most common vehicle that genes use for "splicing"; that is, alternating
what protein they produce. Proteins do the work of the body, such as making
blood vessels or insulin.
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- Researchers once assumed that one gene encoded one protein.
They now know that each gene encodes many proteins. The importance of this
splicing was made even clearer when the human genome mapping projects predicted
that humans have only about 30,000 genes rather than the previous estimate
of 100,000.
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- For example, in a paper published in the December 1999
issue of Nature Biotechnology, John Reed of the Burnham Institute in La
Jolla, California, explains that a gene called "bcl-x" can splice
one way to cause cell death, and another way to turn off programmed cell
death, also known as apoptosis.
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- Zinc fingers bind to certain DNA sequences inside a gene,
which results in a specific splice variance.
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- "It's a very powerful science, and it's enabled
by technology that mimics every organism on the planet," Lanphier
said. "It has evolved to regulate or control all the information contained
in DNA."
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- The ability to engineer zinc fingers to specifically
turn on or off a gene function was first discovered by Carl Pabo at the
Massachusetts Institute of Technology. Pabo is now chief scientific officer
at Sangamo.
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- Sangamo has demonstrated it can turn genes on or off
using zinc fingers in about 500 genes.
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- The company's effort in cardiovascular disease is one
of the closest to becoming a human therapy.
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- With help from researchers at Yale, Sangamo is working
on ways to combine gene therapy with zinc finger technology in order to
grow new blood vessels for heart patients. They also hope to do the opposite
-- cut off blood vessel growth -- in cancer tumors.
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- Researchers at Yale have developed "vectors"
(vehicles made of viruses altered to be harmless) to carry genes that produce
zinc finger proteins into the nucleus of cells, said Frank Giordano, an
assistant professor of medicine at the Yale University School of Medicine
and the director of cardiovascular gene therapy.
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- These zinc fingers are engineered to bind to the gene
that produces a growth factor essential for blood vessel growth called
vascular endothelial growth factor, or VEGF, Giordano said.
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- "The potential for this is huge," said Giordano,
who is not on the Sangamo payroll but consults for Edwards Life Sciences,
a company that collaborates with Sangamo. "It's a whole new direction
for gene therapy."
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- Lanphier said Sangamo is on track to file an Investigational
New Drug Application (IND) for the cardiovascular gene therapy with the
FDA by 2003.
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- Sangamo's effort to find an obesity therapy may also
make its way to FDA trials in the next several years.
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- By experimenting with zinc fingers, Sangamo researchers
were able to identify one specific splice variant of a protein called PPARgamma
as the one responsible for making new fat cells. Now, scientists are generating
zinc fingers that could specifically turn off that splice variant.
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- "That could not have been done with any other approaches,"
Lanphier said.
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- One big caveat to the technology, Giordano said, is that
it won't work with diseases caused by mutated genes, such as sickle cell
anemia, some forms of cancer or cystic fibrosis. It will work only with
normal genes that happen to be producing too much or too little of a particular
protein.
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- Sangamo is the first company in the zinc finger field
and dominates the intellectual property rights. It recently acquired Gendaq,
the only other company to attempt to make zinc finger technology into a
business venture.
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- Sangamo has also obtained licenses for intellectual property
from MIT, Johns Hopkins and Scripps Research Institute.
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- Zinc fingers can also help researchers find out the function
of genes by turning them on or off in animals. Sangamo is collaborating
with more than 20 pharmaceutical and biotech companies to discover gene
function.
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- The company has about $64 million in the bank. If it
doesn't buy any more companies, that will last a few years at their current
burn rate of approximately $5 million per quarter.
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- http://www.wired.com/news/medtech/0,1286,50100,00.html
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