From: Walter Watts (wlwatts@cox.net)
Date: Sun Feb 10 2002 - 08:55:47 MST
How to Turn On a Gene
By Kristen Philipkoski
2:00 a.m. Feb. 6, 2002 PST
A California biotech company has a technology that seems like a killer
app for gene therapy: It can turn any gene on or off.
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.
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.
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.
"Once that biology is done ... Sangamo will be the beneficiary," said Ed
Lanphier, president and CEO of Sangamo (SGMO).
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.
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.
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.
Zinc fingers bind to certain DNA sequences inside a gene, which results
in a specific splice variance.
"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."
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.
Sangamo has demonstrated it can turn genes on or off using zinc fingers
in about 500 genes.
The company's effort in cardiovascular disease is one of the closest to
becoming a human therapy.
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.
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.
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.
"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."
Lanphier said Sangamo is on track to file an Investigational New Drug
Application
(IND) for the cardiovascular gene therapy with the FDA by 2003.
Sangamo's effort to find an obesity therapy may also make its way to FDA
trials in the next several years.
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.
"That could not have been done with any other approaches," Lanphier
said.
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.
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.
Sangamo has also obtained licenses for intellectual property from MIT,
Johns Hopkins and Scripps Research Institute.
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.
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.
-- Walter Watts Tulsa Network Solutions, Inc. "To err is human. To really screw things up requires a bare-naked command line and a wildcard operator."
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