Martin Nowak
Martin's Snakes
“Common Blood Thinners Could Combat Cobra Venom”. Science 18 July 2024
“When a snake sinks its fangs into flesh and injects its deadly venom, some of the toxins start to tear through tissues almost immediately. The destruction these toxins can wreak leaves some 400,000 people maimed by snakebites every year. And antibody-based antivenoms, which are the current gold standard of care, are largely powerless to prevent these disabilities. Now, researchers have discovered that a common blood thinner can thwart these toxins in cells and mice—and could one day do the same for people.
In their research, published yesterday in Science Translational Medicine, the team showed that a blood thinner called heparin and related compounds are highly effective at stopping cobra venoms from killing tissues and cells. For Blair Perry, a biologist at the University of California, Santa Cruz who didn’t participate in the new study, the new findings are “exciting” and could open the door to a new way of developing antidotes for other venomous species.
Snakebite is already considered a neglected tropical disease, one that predominately impacts rural populations in Africa and South and Southeast Asia. But even within snakebite, morbidity is somewhat overlooked. “It’s a neglected area in a neglected disease,” says Shirin Ahmadi, who specializes in the study of skin cell death at the Technical University of Denmark and didn’t participate in the study. “It seems like if it’s not immediately fatal, it’s not the main focus of our efforts.”
Unfortunately, current treatments for bites do little to stop venoms from creating lesions, which can cause permanent limb damage or even require amputation. In most cases, people arrive at hospitals hours to days after a bite, when “it’s almost too late for the antibodies to be able to work,” says study co-author Nicholas Casewell, a biologist with the Liverpool School of Tropical Medicine (LSTM). Another problem is that the antivenoms’ proteins are so large they don’t make their way into the external tissues where lesions occur.
Further complicating matters is the fact that snake venoms are complex mixtures of dozens of components, and despite decades of research, it remains unclear exactly which are responsible for causing lesions. So, Casewell and other researchers from LSTM and the University of Sydney used the gene-editing tool CRISPR to analyze how human cells respond when attacked by the venoms of red and black-necked spitting cobras, African species known to cause devastating injuries even when antivenom is administered. Knocking out genes involved in the production of heparan sulfates—sugars commonly found in human cell membranes and the scaffolding that supports cells—made the cells resilient to the venoms. That indicated the toxins need to bind to these sugars to destroy tissues. And if that’s the case, the researchers wondered whether molecules shaped like these sugars—including heparins and heparinoids—could act as decoys, binding up toxins and preventing them from harming cells.
Sure enough, when the researchers tried to do this by “flooding” human cells with heparin and heparinoids, the venom toxins stuck to the drugs, preventing them from destroying cells. Heparinoids also reduced the size of venom-induced lesions in mice, even when injected to the animals a few minutes after the venom. The most effective drug was tinzaparin, a $60 per dose heparinoid commonly used to treat excessive blood clotting, which reduced the size of the animals’ wounds by 94% when injected alongside the venom.
Further analyses revealed the primary toxins responsible for forming lesions are three-finger toxins—which are commonly found in the venoms of cobras and many of their relatives. Indeed, when the researchers tested heparin and heparinoids against the venom of three other cobra species native to parts of Asia, the drugs were similarly effective.
A strength of the CRISPR approach, Perry says, is this ability to discover compounds to create a more universal treatment. “It might mean that we can start to create more generalizable antivenoms that don’t rely on being closely matched to the species that are in a particular area.”
However, the drugs didn’t work at all against viper venoms, which generally don’t contain three-finger toxins—and, therefore, must liquefy tissue some other way.
Still, because heparinoids are already approved and sold in pharmacies, clinical trials to test their utility against many species’ venoms could be straightforward and speedy, Casewell says. And if ultimately approved for use in snakebites, the treatment would be especially beneficial for rural communities, where hospitals are scarce. “People could go to the nearest pharmacy to get an injection” to help treat a bite, Casewell says.
Although heparinoids cannot be considered a replacement for antivenoms for preventing death, Ahmadi agrees they could be very useful in saving people with fewer resources in more remote locations. “It’s something that’s easy to use in the field and buys us a few hours until they get to the hospital.”
“When a snake sinks its fangs into flesh and injects its deadly venom, some of the toxins start to tear through tissues almost immediately. The destruction these toxins can wreak leaves some 400,000 people maimed by snakebites every year. And antibody-based antivenoms, which are the current gold standard of care, are largely powerless to prevent these disabilities. Now, researchers have discovered that a common blood thinner can thwart these toxins in cells and mice—and could one day do the same for people.
In their research, published yesterday in Science Translational Medicine, the team showed that a blood thinner called heparin and related compounds are highly effective at stopping cobra venoms from killing tissues and cells. For Blair Perry, a biologist at the University of California, Santa Cruz who didn’t participate in the new study, the new findings are “exciting” and could open the door to a new way of developing antidotes for other venomous species.
Snakebite is already considered a neglected tropical disease, one that predominately impacts rural populations in Africa and South and Southeast Asia. But even within snakebite, morbidity is somewhat overlooked. “It’s a neglected area in a neglected disease,” says Shirin Ahmadi, who specializes in the study of skin cell death at the Technical University of Denmark and didn’t participate in the study. “It seems like if it’s not immediately fatal, it’s not the main focus of our efforts.”
Unfortunately, current treatments for bites do little to stop venoms from creating lesions, which can cause permanent limb damage or even require amputation. In most cases, people arrive at hospitals hours to days after a bite, when “it’s almost too late for the antibodies to be able to work,” says study co-author Nicholas Casewell, a biologist with the Liverpool School of Tropical Medicine (LSTM). Another problem is that the antivenoms’ proteins are so large they don’t make their way into the external tissues where lesions occur.
Further complicating matters is the fact that snake venoms are complex mixtures of dozens of components, and despite decades of research, it remains unclear exactly which are responsible for causing lesions. So, Casewell and other researchers from LSTM and the University of Sydney used the gene-editing tool CRISPR to analyze how human cells respond when attacked by the venoms of red and black-necked spitting cobras, African species known to cause devastating injuries even when antivenom is administered. Knocking out genes involved in the production of heparan sulfates—sugars commonly found in human cell membranes and the scaffolding that supports cells—made the cells resilient to the venoms. That indicated the toxins need to bind to these sugars to destroy tissues. And if that’s the case, the researchers wondered whether molecules shaped like these sugars—including heparins and heparinoids—could act as decoys, binding up toxins and preventing them from harming cells.
Sure enough, when the researchers tried to do this by “flooding” human cells with heparin and heparinoids, the venom toxins stuck to the drugs, preventing them from destroying cells. Heparinoids also reduced the size of venom-induced lesions in mice, even when injected to the animals a few minutes after the venom. The most effective drug was tinzaparin, a $60 per dose heparinoid commonly used to treat excessive blood clotting, which reduced the size of the animals’ wounds by 94% when injected alongside the venom.
Further analyses revealed the primary toxins responsible for forming lesions are three-finger toxins—which are commonly found in the venoms of cobras and many of their relatives. Indeed, when the researchers tested heparin and heparinoids against the venom of three other cobra species native to parts of Asia, the drugs were similarly effective.
A strength of the CRISPR approach, Perry says, is this ability to discover compounds to create a more universal treatment. “It might mean that we can start to create more generalizable antivenoms that don’t rely on being closely matched to the species that are in a particular area.”
However, the drugs didn’t work at all against viper venoms, which generally don’t contain three-finger toxins—and, therefore, must liquefy tissue some other way.
Still, because heparinoids are already approved and sold in pharmacies, clinical trials to test their utility against many species’ venoms could be straightforward and speedy, Casewell says. And if ultimately approved for use in snakebites, the treatment would be especially beneficial for rural communities, where hospitals are scarce. “People could go to the nearest pharmacy to get an injection” to help treat a bite, Casewell says.
Although heparinoids cannot be considered a replacement for antivenoms for preventing death, Ahmadi agrees they could be very useful in saving people with fewer resources in more remote locations. “It’s something that’s easy to use in the field and buys us a few hours until they get to the hospital.”