December 6, 2023

Scientists have identified a potential antidote to one of the most venomous mushrooms, the death cap mushroom. Using CRISPR, a team found that a chemical already approved by the FDA could neutralize toxins and save lives in tests on mice — but there were some problems.

In the human environment, potentially toxic substances need to be clearly labeled and stored carefully so that people don’t accidentally ingest them — but nature has no such safeguards. Amanitaor death cap, grow alongside what look like some edible mushrooms, causing many accidental poisonings.

The initial symptoms are gastrointestinal symptoms that look like other forms of food poisoning — vomiting, diarrhea, and nausea — and subside after a few days. More severe symptoms develop later, leading to liver and kidney failure, with a high mortality rate. There is currently no antidote, but drastic measures such as organ transplants can save lives.

Now, there may be hope for a new treatment. Researchers at Sun Yat-sen University in China have identified the molecular target of the death cap’s key toxin alpha-amanitin and found a compound that blocks it. Most importantly, the compound has been widely used in medicine.

The team first used the CRISPR-Cas9 gene-editing technique to create cultures of human cells, each mutated in a different gene. These cells were then systematically exposed to alpha-amanitin, and the surviving cultures could help pinpoint the specific genes and enzymes by which the toxin works.

Using this technique, the scientists targeted a gene called STT3B. It encodes an enzyme that plays a key role in adding sugar molecules to proteins, but cell cultures lacking the gene were harmless to the toxin. The conclusion was that α-amanitin needed this molecular pathway to enter cells, so blocking it prevented most of the damage. Previously, there was no indication that STT3B was involved in death cap toxicity.

Next, the researchers screened thousands of compounds to find one that could block STT3B. This process led them to a dye called indocyanine green (ICG), a dye used in medical imaging. Sure enough, tests on human cells, liver organoids and live mice showed that ICG could block the toxic effects. About 50 percent of the treated poisoned mice survived, compared with 90 percent of untreated poisoned mice.

Discovering the mechanism of toxicity and ways to block it is very promising, especially since the compound is already FDA-approved and widely used. But of course there are some caveats. For one thing, testing on humans would require someone who has eaten the death cap, which means scientists will have to wait for people to go to the hospital.

But the biggest problem is that by then it may be too late. The team tested giving the antidote at different times after ingesting the mushrooms, and found that it worked better if taken within one to four hours—but people often don’t know they’re poisoned so quickly, and go to the hospital a few minutes later. diva.

Still, it’s an important step toward new treatments. CRISPR screening techniques could be used to find other antidotes. Some of the same scientists have previously used the method to identify drug candidates to combat the box jellyfish’s venom.

The study was published in the journal natural communication.

source: nature (1),(2)