Research by a collaborative group of
scientists from UC San Diego School of Medicine, UC San Francisco and Wake
Forest School of Medicine has led to identification of an existing drug that is
effective against Entamoeba histolytica. This parasite causes amebic dysentery
and liver abscesses and results in the death of more than 70,000 people
worldwide each year.
A team
of researchers from UCSF and UC San Diego has identified an approved arthritis
drug that is effective against amoebas in lab and animal studies, suggesting it
could offer a low-dose, low cost treatment for the amoebic infections that
cause human dysentery throughout the world.
Based
on these results, the team has received Orphan Drug Status for the drug, known
as auranofin, from the U.S. Food and Drug Administration, and has applied for
approval to start clinical trials to treat both amebiasis and the parasite
Giardia in humans.
The
findings, which showed that auranofin inhibited growth of the parasiteEntamoeba
histolytica in lab tests as well as two rodent models of the disease,
highlight the importance of screening existing drugs for new purposes,
especially for neglected diseases, the researchers said. Findings will be
reported in the June 2012 issue of Nature Medicine and were
selected for advance online publication on the Nature web
site.
The
combination of an off-patent drug and decades of clinical safety data offers
the possibility of providing a lower-cost solution worldwide with fewer side
effects or risks of bacterial resistance than the current therapy, according to
co-senior author James McKerrow, MD, PhD, a professor of pathology in the UCSF
Sandler Center for Drug Discovery.
"When
we're looking for new treatments for the developing world, we start with drugs
that have already been approved," said McKerrow, who co-authored the paper
with Sharon Reed, MD, of UC San Diego and first author Anjan Debnath, PhD, of
UCSF. "If we can find an approved drug that happens to kill these
organisms, we've leapfrogged the development process that goes into assessing
whether they are safe, which also makes them affordable throughout the
world."
Each
year, 50 million people worldwide contract amebiasis through contaminated food
or water, making it the third leading cause of illness and fourth leading cause
of death due to protozoan infections worldwide.
Most of
the 70,000 deaths each year are in developing countries, where children are at
greatest risk of severe illness. The parasite Giardia also infects between 6
percent and 8 percent of all children in developing countries, causing
diarrhea, abdominal cramps and dehydration.
Both
amebiasis and giardiasis are currently treated with the antibiotic
metronidazole, which has side effects that include nausea, vomiting, dizziness
and headache.
The new
drug, auranofin, has been used as a twice-daily oral therapy for adults with
rheumatoid arthritis since 1985, and has been shown to be safe at that dosage.
The researchers' laboratory studies indicated that auranofin would be about ten
times more potent than the current treatment for dysentery, meaning it could be
given at low dose, and on a one-time or limited basis.
"This
is a drug that you can find in every country," said Debnath, a
postdoctoral fellow at UCSF who led the research and is first author on the
paper. "Based on the dosage we're seeing in the lab, this treatment could
be sold at about $2.50 per dose, or lower. That cost savings could make a big
difference to the people who need it the most."
International
Collaboration
The
research stemmed from a joint effort among several labs at UCSF that are
affiliated with the California Institute for Quantitative Biosciences (QB3) on
UCSF's Mission Bay campus, as well as with the pathology departments in UC San
Diego and in the Instituto Politecnico Nacional, in Mexico.
At
UCSF, McKerrow's team, which focuses on infectious diseases in the developing
world that are not research priorities for pharmaceutical companies, set out to
create a screen to identify small molecule drugs that would kill amoebas
safely.
The key
breakthrough, McKerrow said, was Debnath's development of a high-throughput
screen that could be conducted in an oxygen-free, or anaerobic, environment, to
mimic the amoeba's natural environment. Debnath was working at the time with
Reed's lab, at UC San Diego, studying the impact of protease inhibitors on
amebiasis, and realized he needed to be able to screen thousands of compounds.
Because
of the need for an oxygen-free environment, most tests on amoebas are conducted
in small batches, testing one or two compounds at a time. The modern approach
to these tests – conducting thousands of screens at once – had never been done
in an anaerobic environment. So Debnath reached out to the UCSF Small Molecule
Discovery Center in the UCSF School of Pharmacy and QB3, which uses technology
from the pharmaceutical industry to help bioscience researchers screen the
targets they discover against potential therapies. Together, they modified the
standard screen so it could be used in an anaerobic environment.
The
second lucky stroke was a call McKerrow received during the project from Iconix
Biosciences, a Menlo Park, CA, company that was going out of business. Iconix
offered the Sandler Center its screening library of 900 compounds – each in its
own vial –that have been approved by the FDA for human use.
With
more than half of the FDA-approved compounds at their disposal, the team worked
with the Small Molecule Discovery Center to screen the drugs against amoebas.
The
results were startling: The drug was 10 times more potent in the screens
against E. histolytica than the current treatment.
"The
top hit was this drug auranofin, which caught our attention for a couple of
reasons," McKerrow said. "First, it was more effective than the
current drug, and importantly, it was a drug that has been given to people
since 1985. So we knew it could be taken orally and was safer than the current
drug for amoebas."
Beyond
the Lab
Thus,
they knew they had a safe drug that was effective, but would it work outside of
a test tube? At UC San Diego, Reed's lab had developed a mouse model for
amebiasis in the colon, which the parasite infects first, and in Mexico,
researchers had developed a hamster model that showed the impact of amebiasis
on the liver. In both tests, this was the most effective drug they had ever
seen, markedly decreasing the number of parasites, damage from inflammation and
the size of liver abscesses at a very low dosage.
With
the much-coveted "proof of principle" in hand, Debnath wrote to the
FDA for approval of auranofin for Orphan Drug Status – an FDA program that
fast-tracks new drugs that demonstrate promise in treating a neglected or
orphan disease, defined as either fewer than 200,000 cases in the United States
or those that are not expected to recover the costs of developing and marketing
a treatment.
The
team then worked with researchers at the Wake Forest School of Medicine to show
that auranofin inhibits E. histolytica thioredoxin reductase –
an enzyme involved in defense against damage caused by oxygen metabolism –
making the parasite more susceptible to oxidative stress.
More
information: http://dx.doi.org/
… 1038/nm.2758
Provided
by University
of California - San Diego
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