午夜福利1000集合

SIX days a week it鈥檚 just an ordinary room in an ordinary London hospital.
But on Tuesdays it becomes a place of nightmares. This is the National Prion
Clinic at St Mary鈥檚 Hospital, the heart of Britain鈥檚 efforts to solve its CJD
problem. Patients are referred here from hospitals in their home town and spend
a few days having diagnostic tests. Then they鈥檙e sent home. Beyond that there鈥檚
little anyone can do. There is no cure for Creutzfeldt-Jakob disease. If you鈥檝e
got it, you鈥檙e going to die.

If this were any other rare disease things might stay that way. After all,
there are dozens of equally rare fatal disorders with no hope of a cure. But
that was before the form that traces its ancestry directly back to mad cow
disease, variant CJD, began picking people off in the mid-1990s.

The link with mad cow disease makes variant CJD different. It鈥檚 still less
common than 鈥渙rdinary鈥� CJD, the type that runs in families or strikes the
middle-aged out of the blue. Yet it has taken on a meaning out of all proportion
to its prevalence. It鈥檚 easy to understand why鈥攙CJD is a man-made,
food-borne disease that strikes young, healthy adults. What鈥檚 worse, it could
have been avoided. But for a decision to bulk out cattle feed with cheap
slaughterhouse waste, vCJD would never have happened.

For this reason, there鈥檚 a feeling that we are somehow owed a cure. It鈥檚
possible the British government could deliver one (see 鈥淟icence to cure鈥�).
But the best hope of a cure has more do with pragmatism than a sense of
obligation. A couple of drugs firms are starting to realise that there are
similarities between vCJD and other, much commoner diseases. If they鈥檙e right,
prion diseases could be a proving ground for lucrative drugs against
Alzheimer鈥檚, diabetes and other illnesses. And one of the scraps that could fall
from the table is a cure for vCJD.

Under normal circumstances the pharmaceuticals industry wouldn鈥檛 be
interested in vCJD. According to the latest figures, there have been 106 cases
in Britain and four elsewhere. Even though there are plenty of potentially
promising treatments emerging from labs all around the world, including vaccines
and compounds to stop the march of prions from gut to brain, drugs companies
wouldn鈥檛 be able to sell enough of them to recoup the colossal cost of
developing and licensing a new drug鈥攁n average of 拢350 million.

True, thousands of BSE-infected carcasses entered the food chain in Britain
and elsewhere. So nobody knows how many people have been exposed to tainted
beef, nor how many will eventually succumb to the disease. Yet vCJD is unlikely
to become a regular target for the pharmaceuticals industry. 鈥淓ven if there鈥檚 an
epidemic, and by that I mean tens of thousands of cases, there鈥檚 still no
market,鈥� says John Collinge, head of the Prion Unit at Imperial College, London
and Britain鈥檚 unofficial CJD supremo.

All the more remarkable, then, to hear what鈥檚 going on at the Serono
Pharmaceutical Research Institute in Geneva, part of Europe鈥檚 biggest and most
successful biotechnology company. Two years ago, Serono lured prion expert
Claudio Soto away from New York University鈥檚 Medical Center and set him to work
on CJD. To some it looked like an odd decision. Serono plays by the same rules
as other drugs companies, and a cure for vCJD would be no more profitable for it
than for anybody else.

So what does Serono know that the others don鈥檛? The company鈥檚 reason for
ploughing time and money into vCJD is based on a calculated gamble. If it pays
off, it could deliver huge profits to Serono while handing us a cure for
vCJD鈥攅ven if there are only a smattering of new cases.

The gamble is this. Variant CJD starts when misshapen rogue forms of a
protein, named prion protein, find their way into the nervous system. These
rogue prions go about refolding our natural form of the protein into their own
rogue shape, and the misfits clump together into toxic aggregates. Soto belongs
to a growing band of scientists who see vCJD as just one of a broader class of
diseases caused by misfolded proteins. He thinks that if he can work out how to
prevent or reverse the misfolding process, then he can go on to tackle
Alzheimer鈥檚, diabetes, Parkinson鈥檚, motor neuron disease, cystic fibrosis and
around 20 other disorders.

All these diseases share a common biological characteristic: the affected
organ becomes clogged up with clumps or plaques of protein. With Alzheimer鈥檚 you
get plaques of beta amyloid, with Parkinson鈥檚 it鈥檚 a protein known as tau. With
other diseases, such as type II diabetes, the kind that strikes in adulthood,
the role of protein clumps is more controversial
(New Scientist 15 September, p 7).
But Soto thinks the clumps, and the way cells commit suicide,
look remarkably similar in all these diseases. It鈥檚 a view shared by other
academic scientists, notably Stanley Prusiner who won a Nobel prize for his work
on prion disease. Prusiner, who works at the University of California in San
Francisco, also sees CJD as a model for Alzheimer鈥檚. But Serono was the first
drugs company to act on the idea.

There is still some debate about what initiates misfolding, and whether the
clumps themselves are a direct cause of disease. In many of these diseases it鈥檚
possible that clumping is actually a defence mechanism, a way for the cells to
protect themselves against some other toxic attack. But there is no doubt that
the clumps are intimately associated with widespread cell death in the diseased
organ. In Alzheimer鈥檚, Parkinson鈥檚 and vCJD, the clumps occur in brain cells. In
motor neuron disease they鈥檙e in the nerve cells that control the muscles. In
diabetes they鈥檙e in insulin-producing cells.

If misfolded proteins are the underlying cause, they鈥檙e also a target for
treatment. Stop the protein misfolding in the first place or, better still, make
it revert to normal once it鈥檚 gone awry, and you鈥檝e got a chance of preventing
or curing the disease. Soto thinks he knows how to do this. He says that in most
protein folding diseases, the misfolded molecules contain abnormally long
stretches of a 3D protein structure called beta-sheets. These are stiff panels
like pieces of corrugated iron, which have a tendency to stack up in laminated
clumps. This stacking is what makes the clumps so tough and indestructible. It
stabilises the beta-sheet and locks the proteins in a skewed configuration.

Soto鈥檚 strategy is to disrupt the beta-sheets using molecules called 鈥渂reaker
peptides鈥�. These are short lengths of protein that have a similar sequence to
the misfolded sections of the target protein鈥攂ut with one crucial
difference. They have a bulky chemical group that sticks up from the surface
like a knob on a knuckleduster. When the breaker peptides fold themselves into a
beta-sheet and stack up with the rogue clumps, the awkward shape destabilises
the rogue regions so they flip back to their regular structure
(see Diagram).

With this strategy Soto鈥檚 group has dissolved protein clumps in animal models
of Alzheimer鈥檚 disease. They鈥檝e done the same for mice with scrapie. And they鈥檝e
untangled prion proteins extracted from the brains of vCJD victims after a
post-mortem, making the deadly molecules completely harmless.

There鈥檚 a long way to go before we know if Soto鈥檚 approach will work for
patients. But Serono says the first experimental drug from the programme is
almost ready for pre-clinical trials, perhaps as early as next year. And it鈥檚
good news for vCJD victims, because the first drug will be designed to untangle
misfolded human prions.

There are two reasons for going after vCJD first. Thanks to the flurry of
research after the identification of the disease, it鈥檚 the best understood of
all the protein folding diseases. And secondly, it will be a lot easier to do
clinical trials in vCJD patients. CJD is rare, progresses quickly and is
invariably fatal. More importantly there鈥檚 absolutely nothing on the market to
help people who鈥檝e got it. That means the regulatory hurdles for a clinical
trial will be low. Serono intends to use vCJD as a test bed for promising
compounds before trying them out on diabetes or Alzheimer鈥檚. 鈥淚f you really want
to attack this problem, you start at the easiest point, and that鈥檚 vCJD,鈥� Soto
says.

Mark Purcell, a pharmaceuticals industry analyst at Bank of America, says the
Serono approach could pay off big time. Alzheimer鈥檚 and type II diabetes are
鈥渂lockbuster鈥� diseases for which successful drugs can expect billion dollar
sales. He also believes the approach is scientifically sound, though he says
there are some uncertainties. It鈥檚 not clear, for example, whether all the
misfolded protein responds to the drug, or if the clumps cause cells to die, or
are even a defence against prion disease. In these cases, at best you鈥檇 have a
delaying tactic, at worst you could exacerbate the problem.

Serono鈥檚 experimental drugs are at least five years away from the market. But
the Swiss company isn鈥檛 alone in seeing CJD as a gateway to the riches of
Alzheimer鈥檚 disease. In the neurology unit of the University of G枚ttingen,
Germany, 27 CJD patients鈥攁ll with the classical form rather than the new
variant鈥攁re enrolled on a drugs trial that could result in the first CJD
drug. The phase III trial, which is the final stage of testing before a drug can
be licensed, involves flupirtine, a compound developed by German company Asta
Medica. Flupirtine is supposed to stop brain cells from committing suicide,
which some researchers believe is what destroys the brains of CJD patients. It鈥檚
probably what happens in Alzheimer鈥檚.

The trial will end once 30 patients have tested the drug. The study鈥檚
coordinator, Hilmar Prange, says that will be before the end of the year, and
that it will only take a couple of weeks to analyse the results. If the results
are good, Asta Medica will ask for immediate clearance to re-license flupirtine
as a CJD drug, for both classical and variant forms. Then Asta Medica will move
on to Alzheimer鈥檚. And the good news is there are almost no research and
development costs to recoup because the company already sells flupirtine as a
painkiller and muscle relaxant under the brand name Katadolon.

Not everyone is convinced that flupirtine will help. Fred Cohen, a protein
chemist in Stanley Prusiner鈥檚 group, says it鈥檚 not clear that brain cells commit
suicide in CJD, in which case the drug isn鈥檛 going to help. He also points out
that it鈥檚 only a stalling tactic. 鈥淚t鈥檚 not going after the problem, it鈥檚
sticking a Band-Aid on it.鈥�

But if flupirtine makes it onto the market as a CJD drug, things will have
changed for the better. At least patients will no longer be sent home from the
National Prion Clinic in London with nothing but a death sentence. The drug
they鈥檙e given may only delay their eventual decline. But maybe that delay will
buy them enough time to see the real cure that they鈥檙e owed come to market.

Perhaps the only people who fully understand what a cure would mean are those
who have already lost a family member to vCJD.

Frances Hall lives in Chester-le-Street, County Durham. Her son Peter died in
1996 after a year-long illness. He was diagnosed with vCJD at the post-mortem.
He was 20 years old.

Frances, who now runs the Human BSE Foundation support group, says that a
cure would spare the families of future victims the most frightening, harrowing
experience imaginable. But she and her family have another reason to hope for a
cure. They might all have eaten the beef that killed Peter. 鈥淚 either bought,
cooked or fed Peter something infected. That means another family member might
catch it too.鈥� She lives in constant fear that her other son, John, husband
Derek, or even herself will start showing symptoms.

HOW much would it cost the British government to cure vCJD? According to John
Collinge, head of the prion unit at Imperial College in London, as little as a
few million pounds.

Collinge鈥檚 group is screening thousands of compounds for activity against
human prions. GlaxoSmithKline provides the compounds and technical help but
otherwise the programme depends on public funding. Collinge assumes taxpayers鈥�
money will be made available to turn promising leads into products.

He claims the cost of his project to find a drug and get it licensed will be
just 拢10 to 拢20 million. This is based on the fact that the most
expensive part of drug development鈥攃linical trials involving hundreds of
patients and lasting several years鈥攚on鈥檛 be possible with vCJD. Very few
people get the disease, and those who do deteriorate quickly. There鈥檚 also no
need to go through the normal process of proving the new drug is better than
existing therapies because there aren鈥檛 any.

If Collinge is right, a publicly funded cure looks feasible. It would add at
most 拢4 million to the 拢30 million a year the government already
spends on CJD research. 鈥淚t鈥檚 a drop in the ocean, and I think a lot of people
would agree it would be money well spent,鈥� says Collinge.

But industry insiders doubt his figures. Mark Purcell, an analyst at Bank of
America, says 拢35 million is an absolute minimum, even for a rare disease
like vCJD. And the government is reluctant to commit to anything. A Department
of Heath spokeswoman says that funding a cure is an issue for the future and for
now the focus is on diagnostics.

There is another possibility though. Several groups around the world are
screening old drugs to see if they might also work for CJD. This would probably
be the cheapest approach. Drugs with an existing licence are presumed to be
safe, so there are hardly any development costs to claw back.

The approach has already made headlines. In August, Rachel Forber from
Newton-le-Willows in Lancashire was reported to have recovered from vCJD after
being given a mixture of malaria drugs and anti-psychotics by Stanley Prusiner鈥檚
group in San Francisco. In Britain the Department of 午夜福利1000集合 is preparing to
start clinical trials within weeks.

However, another CJD victim given the same drugs failed to recover. And it is
possible that Forber may not have vCJD at all, New Scientist can reveal. She has
never visited the National Prion Clinic in London, the only place in Britain
capable of definitively diagnosing vCJD prior to death. She also did not receive
a definitive diagnosis in San Francisco.