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Toxin to the rescue: tapping a deadly botulinum protein to treat neuromuscular disorders.

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In a classic example of medicine harnessing therapeutic powers of a poison, researchers have turned a potent toxin that causes botulism into a successful treatment for a number of neuromuscular diseases and anticipate unleashing it against several more.

Through the decades, Clostridium botulinum has gained notoriety for inducing vomiting, dizziness and sometimes even paralysis and death in people who eat canned goods contaminated with it (SN: 2/7/76, p.93). But since the late 1970s, scientists have partially revamped this bacterium's nasty image by using tiny doses of i is lethal product - called botulinum toxin - to treat individuals who suffer from muscular spasms of the eyes, face, throat, limbs or torso.

The organism follows a growth cycle "pretty unusual" even in the bacterial world, says microbiologist Eric A. Johnson of the University of Wisconsin-Madison's Food Research Institute, the only U.S. facility that produces the toxin for medical purposes. In the lab, cultures of C bolulinum turn a turbid yellow-brown within two days of anaerobic fermentation. Some 24 to 48 hours later, the cultures magically clear - after the organisms commit "mass suicide" by dissolving their own cell walls, releasing the toxin in the process.

While C bolulinum produces seven district neurotoxins, researchers have focused on one they call Type A. This complex protein consists of three functional regions: one that targets a muscle nerve ending and binds to its cell membrane, another that helps the toxin enter the cell, and a third that poisons the nerve ending by blocking its release of acetylcholine, a neurotransmitter that normally signals a muscle to contract.

Neurologists, ophthalmologists and other researchers have discovered over the past 15 years that minute doses of Type A toxin produce a temporary, local paralysis that can provide relief to people affected by certain disorders in which excessive muscle contracting activity causes involuntary twisting, twitching and repetitive movements or abnormal postures. Roughly 100,000 to 200,000 individuals in the United States suffer from these conditions, known as dystonias.

Botulinum therapy "has been the most dramatic thing that has happened to these patients in a great many years," neurologist Roger C. Duvoisin said last November at a National Institutes of Health conference on the clinical uses of the toxin.

Type A botulinum toxin debuted in human medicine at the Smith-Kettlewell Eye Research Institute in San Francisco in 1976, when ophthalmologist Alan B. Scott used it to improve the vision of patients whose eyes crossed or turned outward. This condition, known as strabismus, can lead to double vision and deficient depth perception (SN: 5/7/77, p.296). Since then, researchers have tried the potentially lethal protein in "an ever-widening circle of conditions with muscle spasms," says Duvoisin, chief of neurology at the Robert Wood Johnson Medical School in New Brunswick, N.J.

Toxin injected into specific muscles damps excessive nerve firing in selected tissues just enough to prevent abnormal muscle spasms without producing undesired paralysis. In animals, this therapy substantially" inhibits the release of acetylcholine in most targeted nerve endings, says Lance L. Simpson, head of environmental medicine and toxicology at the Jefferson Medical College in Philadelphia. Because dystonia-affected nerves are usually so overstimulated that even after the toxin blocks most of their nerve endings, these cells retain enough activity to maintain normal muscle function, he says.

Human doses generally range from 0.1 to 0.5 nanograms, well below the 16 nanograms needed to induce even mild botulism poisoning. The treatment's long-term effects remain unknown and require further study However, Duvoisin says, since the immediate and localized side effects of Type A toxin (such as drooping of the upper eyelid or difficulty in swallowing) are transitory, treatable and rarely serious when the toxin is properly administered, botulinum therapy appears safe and "relatively easy"

Indeed, the Food and Drug Administration last February approved Type A treatment for people 13 years and older afflicted with any of three dystonias: strabismus, benign essential blepharospasm (spasmodic closing of the eyelids) and hemifacial spasm (in which one half of the face undergoes sudden muscle contractions). Though the therapy appears promising for other disorders as well, its use in any condition other than those three remains experimental and requires special FDA approval.

Allergan Pharmaceuticals of Irvine, Calif., the only firm marketing Type A botulinum toxin in the United States, is currently seeking FDA consent to use the protein against other neuromuscular illnesses. Though Allergan won't disclose which ones, at the recent NIH meeting a panel of experts reviewing clinical studies of the past decade pronounced the botulinum treatment "safe and effective" for three additional conditions:

* Spasmodic torticollis, the most common dystonia, in which painful neck-muscle spasms twist the head to one side.

* Oromandibular dystonia, characterized by continuous spasms of the jaws, lips and tongue that may cause uncontrollable jaw opening or closing and difficulty in swallowing or speaking.

* Adductor spasmodic dysphonia, in which involuntary closing of the vocal cords interrupts the airstream and produces a strained, hoarse, choppy voice.

Researchers using Type A toxin to treat patients with constricted vocal cords have achieved "quite remarkable success" in restoring vocal fluency, says Audrey L. Holland, a speech pathologist at the University of Pittsburgh School of Medicine. "By causing the vocal cords to become more flexible, [the toxin] allows speech to become more normal," she says.

Botulinum toxin may also offer relief for several other speech disorders, including some stuttering conditions, and for occupational hand dystonias - such as writer's or musician's cramp, in which intensive use of the hands leads to loss of control over the fingers. But while researchers feel optimistic about Type A's therapeutic potential, further studies must assess its effectiveness in these and other dystonias, the NIH panel concluded.

Physicians and psychologists once viewed dystonias as psychologically rooted illnesses, but scientists now believe that some of these disorders stem from an abnormality in the basal ganglia, an area of the brain responsible for smoothness and coordination of movement. The defect could be genetic, a consequence of environmental damage or a result of disease.

Except in certain cases of eye misalignment, Type A botulinum toxin provides only temporary symptomatic relief "and does not address the disturbance in the central nervous system [underlying these disorders]," Duvoisin says. Because new nerve endings sprout after several months - reestablishing communication with the muscles - and the dysfunctional nerve endings eventually recover as well, patients require periodic injections. But the temporary nature of the therapy "is in some ways an advantage," Duvoisin says, "because the toxin's effect does reverse in time, so that there is some protection against overtreatment."

Dystonias have conventionally been treated with other drugs, and sometimes with surgery to sever or remove the troublesome nerves. The NIH panel described both approaches as "minimally effective." Past experience has shown that operations to correct dystonias not only are irreversible and sometimes unpredictable, but also carry the risk of disfigurement for what may be short-lived benefits.

For a patient with blepharospasm, surgical destruction of the nerves causing spasmodic eyelid closings costs $10,000 to $14,000, says O.G. Bruce, former president of the Benign Essential Blepharospasm Research Foundation, Inc., in Beaumont, Tex.

in comparison, treatment with Type A botulinum toxin costs $400 to $1,800 per visit, depending on dosage; patients usually require three or four injections a year. While these expenses do, in time, exceed the cost of surgery, Bruce points out that an operation doesn't provide a full cure either and often requires followup drug therapy

Moreover, some dystonias cannot be treated by surgery because the affected muscles lie in areas too difficult or risky to operate on, such as the neck. In contrast, doctors can easily inject botulinum toxin almost anywhere. That's really what's so wonderful about [the treatment]," Johnson says.

A permanent toxin-based therapy may lie upon the distant horizon. At least one researcher hopes to improve Type A's therapeutic potential by manipulating the molecule.

In unpublished experiments, Simpson has engineered a new agent by removing the toxin's cell-poisoning region and inserting a deadlier substitute: a cell-killing fragment, isolated from a plant toxin called ricin, that works by blocking the cell's ability to make protein. If, when injected, this modified Type A toxin successfully binds and kills overstimulated nerve endings in patients with dystonias, it might provide a one-shot cure, he says.

"Nature has provided us with a starting material [in botulinum toxin]," Simpson says. "But I think if we re-engineer the toxin, we can come up with even better therapeutic agents."
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Author:Chen, Ingfei
Publication:Science News
Date:Jan 19, 1991
Words:1409
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