Toxin to the Rescue: Tapping a Deadly Botulinum Protein to Treat Neuromuscular Disorders
Chen, Ingfei, Science News
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). …