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DOI | 10.1126/science.371.6525.113 |
Decoy toxin harnessed to fight botulism | |
Kelly Servick | |
2021-01-08 | |
发表期刊 | Science
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出版年 | 2021 |
英文摘要 | A new strategy to fight the world's most potent poison has passed its first tests in animals. Two research teams have developed neutered forms of botulinum toxin that chase their deadly counterpart into nerves and disarm it. The treatment, if it works in people, would be the first to reverse the paralyzing effects of the toxin inside cells and might spare patients long periods on a ventilator. “In a life-threatening situation, this will be very, very helpful,” says Brenda Anne Wilson, a toxin microbiologist at the University of Illinois, Urbana-Champaign. Made by bacteria that can grow in improperly preserved food and in infected wounds, the toxin penetrates motor nerves and hacks apart proteins critical for nerve signaling. “It's not killing the neurons, but it silences them,” says Konstantin Ichtchenko, a biochemist at the New York University School of Medicine. In tiny quantities, botulinum toxin can control muscle spasms and relax wrinkles. But a larger dose can paralyze breathing. Botulism is rare, with fewer than 200 U.S. cases logged per year, but the toxin is also a terrifying potential bioweapon. The current treatment, a cocktail of antibodies, can inactivate the toxin in blood, but can't enter nerves. By the time symptoms emerge, some toxin is out of reach. Now, Ichtchenko's team and another led by Min Dong, a neuroscientist and microbiologist at Boston Children's Hospital, have hitched neutralizing antibodies to a modified form of the toxin itself, which is adept at slipping into nerve cells. “We basically just created a Trojan horse,” Ichtchenko says. Harnessing neurotoxins for drug delivery isn't new, but using them to send in antibodies is “very intuitive and very elegant,” says Saak Ovsepian, a neurobiologist at the Czech Republic's National Institute of Mental Health, whose team published a similar approach in 2011 using botulinum toxin to ferry gene-carrying viruses into neurons. To devise its Trojan horse, Ichtchenko's group made three genetic tweaks to a natural form of botulinum toxin that prevent it from slicing up cellular proteins. Dong notes, however, that the disarmed toxin can still cause muscle paralysis at high doses. So his study, headed by microbiologist Shin-Ichiro Miyashita, now at the Tokyo University of Agriculture, combined components of a disease-causing form with a related botulinum toxin that doesn't naturally invade or disable human nerves. The resulting drug caused no toxicity in mice even at doses where a modified version of a common botulinum toxin was deadly. Both teams linked their engineered toxin to a tiny antibody, derived from alpacas, that can inactivate the toxin. Compared with full-size antibodies, nanobodies can be more readily engineered to reach specific targets in cells and better keep their structure once inside, says Anne Messer, a molecular biologist at the Neural Stem Cell Institute. Dong's group injected mice with a lethal dose of botulinum toxin and administered its treatment 9 hours later—when paralysis had already set in. The 10 mice given the highest treatment dose were mobile within 6 hours, whereas untreated mice struggled to breathe and had to be euthanized, the team reports this week in Science Translational Medicine . In another set of experiments, the group linked the modified toxin to two different nanobodies and successfully disarmed two common varieties of botulinum toxin at once. In the same issue of the journal, Ichtchenko's team describes successful tests in mice, guinea pigs, and macaque monkeys. All six monkeys given the treatment were alive 10 days after getting the toxin; none of seven untreated monkeys lived past 3.5 days. James Marks, a molecular biologist at the University of California, San Francisco, notes that in contrast to lab animals that are given a single relatively small botulinum dose, human victims often have a large “reservoir” of toxin in their gut that enters the bloodstream over days or weeks. So even if this approach works, patients will likely also need the approved antitoxin treatment to remove toxin from the blood. Both teams plan to refine their products and seek approval from the U.S. Food and Drug Administration, which can authorize drugs based on animal studies when human efficacy tests aren't ethical. Experimental drugs face “a long, hard road” from animal results to an approved product, Marks says. “But this is where it starts.” |
领域 | 气候变化 ; 资源环境 |
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文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/310421 |
专题 | 气候变化 资源环境科学 |
推荐引用方式 GB/T 7714 | Kelly Servick. Decoy toxin harnessed to fight botulism[J]. Science,2021. |
APA | Kelly Servick.(2021).Decoy toxin harnessed to fight botulism.Science. |
MLA | Kelly Servick."Decoy toxin harnessed to fight botulism".Science (2021). |
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