Box jellyfish (Chironex fleckeri) found in coastal waters from northern Australia and New Guinea north to the Philippines and Vietnam is considered to be one of the most venomous animals on the planet. Box jellyfish stings lead to excruciating pain lasting days, tissue death and scarring at the site of the sting, and with significant exposure, death within minutes. While most jellyfish stings do not lead to death, pain and scarring is quite common. Despite its potent ability to cause pain and death, researchers had very little understanding of how this deadly venom works. This makes it very difficult to understand how it can cause so much pain – and how to develop medicines to block venom actions.
A new research has uncovered that methyl and hydroxypropyl cyclodextrins are potential antidotes for box jellyfish venom. The work began in 2012, when CRISPR genome editing technology systematically enabled turning off each gene in the human genome, and test to see which of these is needed for the jellyfish venom to kill the cells.
While normal human cells exposed to venom die in the laboratory within five minutes, gene-edited cells were identified that could last for two weeks continually exposed to venom. It was found that it is a calcium transporter molecule called ATP2B1, present on the surface of cells that box jellyfish venom needs to target in order to kill human cells. It was also found that four of the top ten genes required for venom action were all part of a pathway that produces cholesterol in cells. Therefore, then the research focused on agents that could bind to cholesterol and remove it quickly.
Some of such agents could completely block the box jelly fish venom’s ability to kill human cells only if added before venom exposure. As for the studied cyclodextrins, it was a breaktrough finding that there is a 15-minute window after venom exposure where venom action blocking was observed. So far, additional studies showed that the selected cyclodextrins can block pain, tissue death and scarring associated with a mouse model of box jellyfish stings.
The research group plans to further elaborate the work to move cyclodextrins as venom antidote forward for human use. As well as developing a topical application at the site of a sting, a potential treatment for cardiac injection in the emergency room in the case of very severe box jellyfish sting cases is envisioned.
Man-Tat Lau et al. “Molecular dissection of box jellyfish venom
cytotoxicity highlights an effective venom antidote” Nature Communications (2019) 10:1655