# Prion Disease Treatment's Early Promise Unravels

Peter Follette

► To cite this version:

Peter Follette. Prion Disease Treatment's Early Promise Unravels. Science, 2003, 299, pp.191-192.
10.1126/science.299.5604.191. hal-01358782

HAL Id: hal-01358782

https://hal.science/hal-01358782v1

Submitted on 12 Feb 2026

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# Prion Disease Treatment's Early Promise Unravels

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.

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 to 30 cases a year, and no one knows where this is going to go.”

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 4½/2 to 5 years, we’ve seen 20 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.”

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

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 penatosan 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

<figure><img src="image_2.png" /><figcaption>Twisted foe. Contorted, toxic prion proteins have so far resisted all medical assaults.</figcaption></figure>

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available for
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**Safe but not so effective.** Quinacrine was widely used as an antimalarial agent, but its antiprion powers have proven fleeting.
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

Peter Follette is a writer in Ville d'Avray, France.