Now, keep up to date
with daily feeds of newly posted stories
about America's Seniors...click on the box
to the left
Test
quickly assesses whether Alzheimer's Drugs
are hitting their target
Newswise — A test developed by
physician-scientists at Washington
University School of Medicine in St. Louis
may help assess more quickly the ability of
Alzheimer's drugs to affect one of the
possible underlying causes of Alzheimer's
disease in humans, accelerating the
development of new treatments.
Scientists used the test to show that an
Alzheimer's drug given to healthy volunteers
reduced production of a substance known as
amyloid beta (A-beta), a normal byproduct of
human metabolism that builds to unhealthy
levels forming brain plaques in Alzheimer's
patients.
The drug candidate, LY450139, which is also
known as semagacestat, is being studied in
clinical trials by Eli Lilly and Company.
Ongoing clinical trials are studying the
effect that semagacestat may have on
cognitive function and biochemical and brain
imaging biomarkers in patients with
Alzheimer's disease.
Washington University researchers wanted to
see whether the new measurement technique,
stable isotope-linked kinetics (SILK), could
detect the study drug's impact on A-beta
synthesis in healthy volunteers.
"Bringing an Alzheimer's disease drug into
clinical trials from tests in animal models
has always been challenging," says study
director Randall Bateman, M.D., a Washington
University neurologist who treats patients
at Barnes-Jewish Hospital.
"We
haven't had a way to quickly and accurately
assess a drug's effects, and that meant
there always had to be some degree of
educated guesswork when it came to setting
the optimal dosage for humans. SILK may help
to eliminate much of that guesswork."
Scientists are unsure whether increased
A-beta production, reduced clearance or a
combination of the two lead to the A-beta
buildup in the brain, a process that many
believe triggers Alzheimer's disease.
Bateman and his colleagues are currently
using SILK to try to answer this question.
Until SILK, there has not been a way to
directly measure the production or clearance
of A-beta.
The efficacy of potential new Alzheimer's
drug candidates has been assessed by
monitoring the cognitive functions of
patients with the disease for extended
periods of time, which require large,
lengthy and expensive studies.
In their double-blind study, scientists gave
20 healthy volunteers varying doses of
either a study drug or a placebo.
At the start of the SILK test, volunteers
were connected to an intravenous drip that
gave them a slightly altered form of the
amino acid leucine, which is a component of
A-beta.
Over the course of several hours, cells in
the brain picked up the labeled leucine and
incorporated it into the new copies made of
A-beta and other proteins.
The scientists took periodic samples of the
subjects' cerebrospinal fluid to determine
how much of the A-beta included altered
leucine.
Tracking the rise of the percentage of
labeled A-beta over time reveals the A-beta
production rate.
Scientists then stop the leucine labeling
but continue analyzing spinal fluid samples.
As the body removed old A-beta and made new
A-beta, the percentage of A-beta containing
altered leucine dropped, revealing the
A-beta clearance rate.
The results suggest a dose-dependent drop in
A-beta production, with an 84 percent
reduction in A-beta production being
measured with the highest study drug dose.
The SILK procedure takes 36 hours, but
provides scientists a more detailed
assessment of amyloid beta production and
clearance levels than they can obtain
through conventional methods.
"You could use a spinal tap to look directly
at the amount of A-beta present in the
cerebrospinal fluid, but we've shown that
natural processes cause A-beta levels to
change dynamically," says Bateman.
"Such changes make it more difficult to
assess the effects of a drug in that
fashion."
The study was funded through a Lilly grant
from a funding program that allowed Bateman
to propose the research and retain control
of it.
Five of the paper's 12 authors are Eli Lilly
employees.
Washington University in St. Louis licensed
its pending patents on SILK to C2N
Diagnostics, LLC, a St. Louis diagnostics
company started by Bateman and senior author
David Holtzman, M.D., the Andrew and
Gretchen Jones Professor and Chair of
Neurology. Bateman and Holtzman's financial
interests in the company are governed by the
university's conflict-of-interest policies.
... ..
...
...