From: TSS (216-119-163-164.ipset45.wt.net)
Subject: Re: Prion Disease Treatment's Early Promise Unravels [FULL TEXT]
Date: January 10, 2003 at 7:38 am PST
In Reply to: Prion Disease Treatment's Early Promise Unravels posted by TSS on January 10, 2003 at 7:13 am:
NEW PERSPECTIVES FOR PRION THERAPEUTICS MEETING:
Prion Disease Treatment's Early Promise Unravels
Peter Follette
Science 2003 299(5604): p. 191-192
http://www.sciencemag.org/cgi/content/summary/299/5604/191?ct
NEW PERSPECTIVES FOR PRION THERAPEUTICS MEETING:
Prion Disease Treatment's Early Promise Unravels
Peter Follette*
PARIS--More than 200 researchers met at a Left Bank hotel in December
for the first international conference
dedicated exclusively to therapeutics for prion diseases. Their
reports, however, dampened hopes of an imminent
solution.
The videotapes showed dramatic improvements in patients being treated for
Creutzfeldt-Jakob disease (CJD). A man whose eyes had rolled
aimlessly behind closed lids now scanned the room and fixed his gaze on
the doctor standing beside him. A woman once mute and inactive
smiled, laughed, and held out her hand to a researcher.
Twisted foe. Contorted, toxic prion proteins have so far resisted all
medical assaults.
CREDIT: OLIVER MECKES/NICOLE OTTAWA/PHOTO RESEARCHERS
Both patients had been treated with the drug quinacrine, one of a handful
of experimental therapeutics for this debilitating disease. But encouraging
as they were, the gains seen on tape
were short-lived, reported Masashi Nakajima, a neurologist at Fukuoka
University in Japan; within weeks of starting treatment, both patients
returned to their previous states.
Jean-Philippe Brandel, a neurologist at the Pitié-Salpêtrière Hospital in
Paris, also reported disappointing results. In a nonblinded study of the
same drug, researchers detected neither
"clinical improvement in the [CJD] patients nor an increase in their
length of survival."
Despite initial hopes for quinacrine and a few other compounds approved
for human use, scientists have been unable to gain the upper hand on CJD,
the most common of several rare, fatal
neurodegenerative diseases thought to be caused by misshapen proteins
called prions. Most CJD cases occur spontaneously in the elderly, although
a propensity for CJD can be inherited.
But it is the still-unfolding outbreak of a variant of the disease--vCJD,
caused by eating infected beef--that has captured public attention and
galvanized research.
Since 1995, vCJD has killed more than 120 people in Europe--and no one
knows how many harbor latent vCJD infections from having eaten tainted beef
during the height of the "mad
cow disease" epidemic in the late 1980s and early 1990s. Experience with
kuru, a prion disease that was spread by ritualistic cannibalism among New
Guineans until the 1950s,
suggests that prion infections can lie dormant for decades. Stanley
Prusiner of the University of California, San Francisco (UCSF), who won a
Nobel Prize for his work on prions, says
that "for the last 41/2 to 5 years, we've seen 20 to 30 cases a year, and
no one knows where this is going to go."
Most researchers believe that all forms of CJD are caused by the same
miscreant proteins. These misfolded prions coerce normal prion proteins to
adopt a pathogenic form, which
ultimately kills neurons and leaves the brain riddled with holes, like a
sponge.
Quinacrine is one of many compounds capable of stopping the spread of
prions in cultured neuroblast cells or in infected lab animals. It stood
out as a drug candidate because it was
immediately ready for testing in CJD patients. Used in people for more
than 60 years, largely as an antimalarial agent for soldiers serving in the
Pacific during World War II, quinacrine
was known to cross the blood-brain barrier.
In 2001, headlines around the world heralded the apparent recovery of
Rachel Forber, a young British woman with vCJD who had flown to San
Francisco to receive the drug. But, like the
Japanese patients in the videos shown at the meeting, Forber's recovery
was transient, and she succumbed to the disease a few months later.
No one knows why quinacrine shows modest, early success in some patients
but fails to halt the disease. Testing conditions have been less than
ideal. High doses of quinacrine can damage
the liver, a side effect that has forced several CJD patients to stop
taking the drug. And in the absence of a blood test for CJD, a diagnosis is
possible only once symptoms appear, when the
damage to the brain is already extensive, perhaps beyond repair. "The
problem with all the quinacrine studies right now," says Prusiner, "is that
we are treating only people ... with
very advanced disease."
Reports at the meeting failed to offer much hope that disappointing
quinacrine results would be offset anytime soon by success with any of the
other drugs that show antiprion activity and
have been approved for human use. A clinical trial in Germany suggests
that the analgesic flupirtine can slow down the cognitive deterioration
seen in CJD patients, but it has no
significant effect on the length of survival. And despite some
encouraging results in experimental animals with pentosan polysulfate, an
anticoagulant that the British High Court ruled
last month could be administered to two teenagers with vCJD, this
compound cannot pass the blood-brain barrier and must therefore be injected
directly into the brain.
With first-generation drugs falling short, researchers are racing to
identify new compounds. Prusiner and his UCSF colleagues plan to screen
thousands of quinacrine analogs over the
next several years for more potent derivatives. Others are trying to
parlay the current explosion of knowledge about prion biology into new
treatments. The approaches on display at the
meeting included methods to prevent the conversion of the normal prion
protein into its misshapen form, ways to nudge the immune system into
fighting prions (an approach once thought
impossible because of people's natural tolerance to the normal prion
protein), and strategies to interrupt the life cycle of prions in cells.
In one such study, Corinne Lasmézas, a researcher with the French Atomic
Energy Commission in Fontenay-aux-Roses, and her colleague Stefan Weiss of
the Gene Center in Munich
targeted a receptor that interacts with the normal prion protein while
it's on the cell surface and that may be involved in its conversion to the
misshapen form. When the researchers
blocked the receptor's expression in infected cells, there was a striking
reduction in the number of malformed prions.
Although most of the therapeutic strategies described at the meeting aim
to rein in the infectious prion particles, some researchers are seeking
ways to repair the structural damage to
the brain that causes the disease's symptoms. In one presentation, Janet
Fraser of the Institute for Animal Health in Edinburgh, U.K., reported that
stem- or fetal-cell transplants can
colonize damaged areas of the brain and restore some lost tissue in
experimental animals.
Intercepting the disease well before it eats away at the brain, however,
would open up the most treatment options. Many people at the meeting
emphasized the dire need for diagnostic tools
that would permit widespread screening for carriers of the infectious
agent. Such tools would signal who should receive compounds--perhaps
including quinacrine--that might prevent
prions from spreading within the brain, or even from reaching the central
nervous system in the first place.
Peter Follette is a writer in Ville d'Avray, France.
TSS
