Toxins as therapy
January 5, 2009
Most people know Botox—the trade
name for botulinum toxin—as a
trendy treatment for facial wrinkles.
Long before its cosmetic use, though,
the toxin became known as a potent muscle
relaxant. Neurologists have used it for
decades, in tiny doses, to treat spasms in the
face or limbs, uncontrolled blinking, and
other conditions. It's become standard
therapy for the abnormal contractions that
often occur in Parkinson's disease or after a
stroke, or in a rarer ailment called dystonia.
Toxins may seem unlikely tools for
doctors. But to VA researcher Paul
Fishman, MD, PhD, they are a treasure
trove of therapeutic potential. The
neurologist and his group at the Baltimore
VA and the University of Maryland are
now studying the use of toxins besides
botulinum, such as tetanus and diphtheria,
to treat disorders involving muscles.
In scientific terms, the toxins studied in
Fishman's lab are proteins made by
pathogenic bacteria. The diseases they
cause are nasty and often lethal.
Botulinum toxin was in Hitler's arsenal. It
was loaded into bombs by Sadaam
Hussein's regime, according to United
Nations reports. It is listed by the Centers
for Disease Control and Prevention as a
prime potential agent of bioterrorism.
Understandably, the debut of botulinum toxin
in health care in the 1970s raised some
eyebrows. Even Fishman was skeptical, to
put it mildly, when he first heard of it being
used to help patients. "I thought people were
nuts. In my training, I had seen people with
botulism. Everyone knew what a powerful
toxin botulinum was. Using it as a therapy
seemed crazy and dangerous."
Fast-forward to 2009. After years of
injecting minute doses of botulinum toxin
into patients' muscles and seeing
remarkable benefits, Fishman is a big
proponent of its clinical use.
"It's an enormously powerful and
effective muscle relaxant," he says. "It's
really been beneficial for conditions where
there are no other effective treatments."
That is part of what triggered his interest
in another toxin: tetanus. It has the opposite
effect on muscles—it activates them—and
Fishman believes it could play an equally
important role in medicine. He and VA
collaborator Chris Matthews, PhD, see the
toxin as a possible tonic for muscles that
have atrophied from disuse. This is common
in patients with severe injuries who are laid
up in bed for long periods. Tiny doses of the
toxin could also be used to energize muscles
weakened by neurological conditions, he
believes. "Could you take a small amount of
tetanus toxin and amplify an inadequate
contraction?" ponders Fishman.
He gives the example of a post-stroke
patient whose hand is locked in a fist.
Botulinum toxin could help ease the grip.
But the patient might still have trouble fully
opening the hand and extending the fingers.
"Could we use tetanus toxin to enhance
their ability to open their hand, activate
those muscles? I view it as complementary
to botulinum toxin," says the researcher.
Tetanus experiments
challenged myth
Given the clinical success of botulinum
toxin, why haven't others thought of using
tetanus toxin in a parallel fashion, as
Fishman envisions? The reason has to do
with vaccination. Experts have assumed that
since almost everyone in Western society is
vaccinated against tetanus, the toxin could
have no effect—good or bad—on people's
systems. Thus, it would be of no use
medically.
Experiments in Fishman's lab showed
otherwise. Even in vaccinated rodents, the
injected toxin evaded antibodies and found
its target: nerve cells that control muscles.
The toxin then works its way inside cells,
where antibodies can't touch it.
Ironically, Fishman's early tetanus
experiments were done with no intention of
using the toxin itself therapeutically. In fact,
his team was using only a segment of the
tetanus molecule—the part that targets and
enters motor neurons—in hopes of using it
to ferry other therapeutic agents into the
cells. The toxic part of the protein was
irrelevant—or so they thought. Once they
realized how good the toxin was at targeting
nerve cells, they decided to repeat their
animal experiments with the whole, toxic
form of tetanus. They noted with great
interest its activating effect on muscles.
Natural toxins becoming
hotter topic for researchers
Fishman says natural toxins are
becoming a hotter topic among researchers.
"There's lots of precedent recently in the
medical literature showing that we can
harness the power of natural toxins," he
notes. He cites the example of diphtheria
toxin, which spurs the production of
antibodies that kill some tumors.
Fishman's team is using diphtheria toxin
in a different way: They are combining it
with the part of the tetanus molecule that
targets nerve cells. The goal is a hybrid
toxin that, like botulinum toxin, could be
used to selectively kill motor neurons.
Fishman is also collaborating with
Homeland Security researchers to develop
antidotes to botulinum toxin. The project is
important for national security, but there
may also be a routine clinical benefit, he
explains.
"I tell patients all the time, I'm going to
be very careful with dose, I'm going to stay
in the lowest ranges, because if I overdose
you, there is no antidote. I'd like to be able
to rephrase that and say, if I overdose you, I
can give you something that will terminate
the action of the toxin."
This article originally appeared in the January 2010 issue of VA Research Currents.