FW: Search for drugs for neuro-diseases

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FYI. Nice to see this new approach being taken!

FWD: Search for drugs for neuro-diseases

Source: Foundation for Biomedical Research; E-Clips #176, 25 June 2002

An unconventional strategy to find new drugs for neurological

diseases

Boston Globe, June 25 - Six hours a day, chemist Craig Justman

and research

assistant Andy Choi examine fruit flies with cell damage similar

to Parkinson's

disease under a microscope, looking for signs that the insects

have benefited from

any of the 900 drugs they are testing. Their hope is that

existing drugs, already

known to be safe for humans, might help the half-million

Americans who have

Parkinson's, a progressive disease that attacks brain cells.

Scientists have long

wondered if such surprise benefits might exist for patients with

various as-yet

incurable diseases, but until recently, few were systematically

looking for them.

Read more. (See below)

----------------------

Breaking drug company rules

A Harvard lab tries an unconventional strategy to find new drugs for

neurological

diseases: Looking in the medicine cabinet

By Anne Barnard, Globe Staff, 6/25/2002

Six hours a day, chemist Craig Justman and research assistant Andy Choi

snip off the heads of fruit

flies with cell damage similar to Parkinson's disease and inspect them

under a microscope, looking

for signs that the insects have benefited from any of the 900 drugs

they are testing.

Drugs like aspirin. Or antacids. Or Viagra.

Their hope is that existing drugs, already known to be safe for humans,

might help the half-million

Americans who have Parkinson's, a progressive disease that attacks

brain cells. Scientists have long

wondered if such surprise benefits might exist for patients with

various as-yet incurable diseases,

but until recently, few were systematically looking for them.

Such experiments are not a big focus at drug companies, since finding

new uses for old drugs is far

less profitable than inventing new medicines. Nor would they fit in at

most academic laboratories,

where randomly testing potential drugs to see what works is often seen

as intellectually inferior to

exploring basic biology or trying to logically deduce a cure.

But now, a handful of scientists are combining academic and industry

strategies as they hunt for

cures for neurological diseases. With funding from patients' groups and

modest but growing

government support, they are venturing into an area long considered the

province of industry - the

nitty-gritty process of drug discovery. But they are taking risks that

pharmaceutical companies

might not - from seeking less lucrative cures to spending time and

money on long-shot ideas.

''Our goal isn't to compete with big pharma - we can't. It's to

complement their work,'' said Ross

Stein, a career drug-industry chemist who left Dupont Pharmaceuticals

last year to run an unusual

new Harvard lab with a mandate to pioneer nonprofit drug discovery in

neurodegenerative

diseases. It was launched with a $37.5 million anonymous gift from a

patient's relative. ''What I'm

trying to do is bring the focus and goal orientation that I've had in

industry and marry that to the

innovation and creativity and free-ranging thinking that you have in

academics.''

Testing already-approved drugs is just one of the underexplored fields

young academics are staking

out, and in that area alone, they have already found some promising

leads.

Working under Stein at the new Laboratory for Drug Discovery in

Neurology, Justman, 33, a

postdoctoral fellow, said he has found that 20 drugs approved for other

conditions seem to protect

the fruit flies from the protein that damages cells in Parkinson's

disease. Dr. Mel Feany, 36, who

developed the genetically altered flies in her lab at Brigham and

Women's Hospital, reports finding

that about a half-dozen other drugs help flies with symptoms that mimic

Alzheimer's disease.

And in a six-month, $1.3 million project funded by the National

Institutes of Health, 1,040

approved drugs and nutritional supplements were screened in 29

different test-tube experiments to

see if they might affect neurological illnesses such as Huntington's

disease, which has attracted

relatively little for-profit research because its patients are a small

market and the diseases are still

poorly understood.

Researchers would not reveal specific results before publication in

scientific journals, partly because

they fear patients might try drugs prematurely; more tests in animals

and humans are needed. But

the NIH-funded tests were fruitful enough that the National Institute

for Neurological Disorders and

Stroke plans to expand the effort, according to Jill Heemskerk, program

director for technology

development. Also this summer, the agency will change the criteria for

some research grants in

order to free academic researchers to pursue practical goals in drug

discovery.

''This is a huge shift for us,'' Heemskerk said. ''We always want

investigators to have this as an

ultimate goal. Now we're saying we want to frankly outright pay for

it.''

The new initiatives come after years of pressure from patients' groups

that point out a broad failure

in drug discovery: Too many potential cures fall into the cracks

between the basic science

traditionally funded by the government and the painstaking work drug

companies do to turn a

promising test-tube reaction into a drug ready to test in humans.

Typically, the path to a new drug starts with a ''target'' molecule in

the body, usually a protein, that

scientists believe has a key function in a disease. Researchers then

try to find chemicals that block

or boost its activity. Academic researchers often help identify targets

or a few potential drugs, but

they usually stop there and try to license their idea to a company.

Companies use expensive robots to screen libraries of tens of thousands

of compounds against

targets; the Harvard lab is one of the few in academics that has this

technology. About.1 percent,

called ''hits,'' have an effect. Only one in thousands will become a

drug. Scientists must find the right

concentration, make sure the dose can reach the needed part of the

body, and test it in animals for

safety and effectiveness. Only then does the most expensive part of

drug discovery, clinical trials,

begin. Just one in five drugs tested in humans makes it to government

approval.

Despite mushrooming research budgets - $30 billion in 2000 - the output

of new drugs by

companies has slowed. For every new drug on the market, companies spend

an average of 11

years and $800 million, according to the Tufts Center for the Study of

Drug Development. Even

Public Citizen, a group skeptical of the industry, puts the figure at

$110 million. And a study

released last month by the National Institute for Health Care

Management Foundation found that

two-thirds of new drugs between 1989 and 2000 were variations on

existing chemicals rather than

novel compounds that work in newly discovered ways.

The problem, scientists in industry, academia and government agree, is

that company shareholders

don't want to try the riskiest ideas, and academic scientists usually

aren't well trained in mass

screening and optimizing drugs. They consider it boring, and their

government funding is not set up

to reward that kind of work.

The movement to change that began with patients, including many with

neurodegenerative diseases.

Finding drugs for these diseases is especially hard because many drugs

that work in the test tube fail

to migrate from the blood to the brain; and because clinical trials in

progressive diseases take longer

and cost more. The last new drug for Parkinson's was approved in the

1960s, and it only treats

symptoms. Drug companies have recently boosted investment in neurology,

investigating 16 drugs

for Parkinson's, but it will take time to pay off. And only two drugs

are in clinical trials for

Huntington's, a disease with a much smaller market.

Five years ago, the Hereditary Disease Foundation started funding

academic researchers to carry

the ball further in research on Huntington's. Other patient groups

followed suit. And soon, the NIH

will start awarding grants to take neurology drug candidates closer to

development.

Carl , director of the foundation's Cure HD Initiative, said he

hopes that in a few years

academic researchers will approach pharmaceutical companies with

''essentially the complete

package: `Here's the drug; here's the proof that it really works in

animals; here's the patents

wrapped around it. What we want you do to, pharmaceutical company, is

run the clinical trials,

manufacture, market and distribute it.'''

Now, said Heemskerk and patient advocates, Harvard associate professor

T. Lansbury Jr.,

chairman of the new lab, has brought a new enthusiasm and focus to the

effort.

''We're not going to have trucks backed up to the [Harvard Medical

School] quad to deliver

drugs,'' Lansbury said. Rather, he said, the lab will act like a small

biotechnology company, moving

research through animal studies and then signing up pharmaceutical

partners. They hope their efforts

will piggyback on the Orphan Drug Act, which gives companies incentives

to develop drugs for

rare diseases. That has increased the number of small-market drugs in

development, but hasn't

solved the problem of getting industry scientists to try long-shot

experiments. Lansbury said

nonprofit researchers can close that gap by approaching companies with

ideas that are well

established, ''quivering on the rim, waiting and ready to drop in.''

Stein said he most relishes the chance to do work that was discouraged

when he worked for

companies, such as looking for molecules that might not work

immediately as drugs but could serve

as tools for further inquiry.

For example, two of the lab's researchers,Yichin Liu and Hilel Lashuel,

recently tested 12,000

compounds against an enzyme thought to be important in Parkinson's -

but whose role is not clear

enough to make it a drug-company target. They found 20 compounds that

stimulated the enzyme

and 20 that repressed it - some likely to be important tools and

possibly even drugs.

The biggest challenge, researchers said, has been getting academics

trained to shine as individuals

to work as a team under a former industry executive.

''There have been tensions,'' Stein said. ''But nothing we can't

handle.''

Anne Barnard can be reached at abarnard@....

This story ran on page C1 of the Boston Globe on 6/25/2002.

© Copyright 2002 Globe Newspaper Company.