[Paleopsych] Wired: Sam Jaffe: Giving Genetic Disease the Finger

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Sat Jul 9 00:05:27 UTC 2005

Sam Jaffe: Giving Genetic Disease the Finger

Scientists are closing in on techniques that could let them safely
repair almost any defective gene in a patient, opening the door for
the first time to treatments for a range of genetic disorders that
are now considered incurable.

The breakthrough, announced in the journal Nature in June, relies on
so-called zinc fingers, named after wispy amino acid protuberances
that emanate from a single zinc ion. When inserted into human cells,
the fingers automatically bind to miscoded strands of DNA, spurring
the body's innate repair mechanism to recode the problem area with
the correct gene sequence.

  A method for fixing miscoded DNA by injecting foreign genes into
cells won headlines three years ago when doctors in France and
Britain announced a handful of successful cures related to X-linked
severe combined immunodeficiency disease, or SCID, also known
as "bubble boy" disease. But that method was ultimately proven

In a paper published earlier this month, scientists at California
biotechnology company Sangamo BioSciences showed that zinc fingers
can be used to erase targeted portions of DNA without risk of
harmful side effects.

"This doesn't just deliver a foreign gene into the cell," said Nobel
Prize winner and CalTech President David Baltimore, who with a
Sangamo paper co-author Mathew Porteus proposed this method to cure
genetic diseases. "It actually deletes the miscoded portion and
fixes the problem."

At the heart of the breakthrough is the concept of "if it's broke,
break it some more." Cells have a method of DNA repair called
homologous recombination, which fixes breaks in the double helix of
our chromosomes. But the process only repairs places where the DNA
has been cut, not where genes have been miscoded.

Using a package of synthesized zinc fingers, cells can be tricked
into doing nano-surgery on their own genes, Sangamo researchers
found. The zinc fingers home in like a guided missile on the exact
spot in the genome doctors are trying to target and then bind to it.
DNA-devouring enzymes then cut through the double helix of DNA at
the exact beginning and end of the targeted gene, and a template of
donor DNA helps rebuild the deleted strand.

While such a therapy has been theorized for years by Baltimore and
others, Sangamo scientists are the first to show test-tube results
with human cells. In a paper published June 2, Sangamo researchers
showed how they were able to correct the defective gene in 18
percent of the T-cells extracted from the body of an X-linked SCID

That should be enough to cure the disease, as it only takes one
corrected T-cell to repopulate a person's immune system with healthy
cells, according to Sangamo.

If successful in trials, Sangamo's technology would be the first
successful gene therapy, three decades after the concept of curing
diseases by tinkering with the genome was first proposed. Most gene
therapy trials have failed because the methods of inserting new
genes into cells (usually with modified viruses as vectors) haven't
proved to be effective enough.

One trial that did succeed, but then ended in tragedy, was a 2002
French X-linked SCID trial that used retroviruses to deliver a new
gene into the patients. The new gene cured the disease in 12
patients, but went on to cause leukemia in three of them. It turned
out the foreign gene, in addition to producing the protein that
vanquishes X-linked SCID, had the unexpected side effect of
sometimes turning on a cancer-causing gene.

Sangamo's technology overcomes that problem. Whereas the French
viruses inserted the foreign gene randomly into the host cell's
genome, the zinc fingers are highly specific and can land only at
the targeted gene.

"They've certainly raised the bar for gene-therapy safety," said
Scott Wolfe, a zinc-finger researcher at the University of
Massachusetts Medical School in Worcester, Massachusetts. He points
out that the early proof-of-principle work was highly toxic to the
cells. The zinc fingers weren't specific enough and they created so
many double-stranded breaks in the DNA that a lot of the cells chose
to commit suicide rather than try to repair all the breaks. "They
really seem to have solved the toxicity problem altogether."

Although X-linked SCID patients will probably be the first to try
the therapy, the technology is extremely versatile for a host of
human diseases. "Right now, its greatest weakness appears to be that
it is optimized for very small patches of gene repair," said
Baltimore. "If it's a long sequence of DNA that has to be fixed,
this might not be the best way to do it."

Nevertheless, there are a lot of ways to attack diseases without
replacing whole genes. Other potential targets for the therapy range
from many types of cancer to cystic fibrosis and even AIDS. "If they
can figure out how to optimize their zinc fingers for any spot on
the genome, this could target any gene you want it to," said Wolfe.

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