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Nanoparticles, enzyme inhibitors and cloned human antibodies are among an array of modern weapons being brought to bear on an ancient killer — the bite of the venomous serpent.

Snakebite poisoning kills between 81,000 and 138,000 people every year, according to the WHO. Depending on the species, victims may suffer paralysis, breathing difficulty, bleeding, heart failure, irreversible kidney damage and permanent disability. The WHO estimates that about 400,000 people annually are left maimed after being bitten by venomous snakes.

Scientists are trying to find ways to make snakebite treatment cheaper, safer and more accessible than the century-old antivenoms that are derived from large animals, usually horses, that are injected with snake venom to induce the production of antibodies. 

Little has changed since 1895 when antivenom was invented by the French scientist Albert Camette to treat soldiers who had been bitten by the Indian cobra. The latest development was a freeze-dried version that is costly but useful for storage in rural areas where there is no energy to run refrigerators.

“In rural areas, it may take patients 6 to 10 hours to reach the hospital.”

José María Gutiérrez, Instituto Clodomiro Picado in Costa Rica

While animal-derived antivenom serum can be life-saving, it carries antibodies that have nothing to do with snakes and can trigger adverse reactions in the human immune system resulting in so-called serum sickness or anaphylactic shock. As a result, treatment with horse-derived antivenom requires specially trained staff and, ideally, a hospital setting.

Existing antivenoms are specific to different snake species, and therefore tend to be expensive and have several limitations associated with biological therapy. Some antivenoms are designed to deal with the venom of several snake species, but none can be described as broad-spectrum.  


Going small for bigger impact


At the Instituto Clodomiro Picado in Costa Rica, José María Gutiérrez has been working with different groups of researchers to develop a toxin inhibitor capable of bridging gaps in the treatment of snakebites, starting with immediate care in resource-poor settings.  

“In rural areas, it may take patients 6 to 10 hours to reach the hospital and by then, the venom would have caused extensive damage,” Gutiérrez says, adding that between half and three-quarters of snakebite deaths happen before the victim is brought to a medical facility with trained personnel and equipment. 

"We want to address that gap by developing nanoparticles that can be given to the victim on the spot, immediately after the bite,” Gutiérrez explains. Inhibitor nanoparticles bind to snake toxins in the blood, “sequestering” them and stopping them from acting on the body.

“Ideally, we could have a nanoparticle cocktail that is capable of binding onto many types of toxins from the medically important snake species,” Gutiérrez says. “The nanoparticle cocktail is not supposed to replace antivenoms but complement their use.”

In a study published in October in PLoS Neglected Tropical Diseases, Gutiérrez and his colleagues describe a broad-spectrum antivenom comprising polymer nanoparticles engineered to sequester the major toxic proteins in poisonous snakes.

Elapids — like cobras, kraits and mambas — have fixed, hollow fangs through which they inject venom. They are differentiated from the viperid family — vipers, adders and rattlesnakes — that have foldable fangs.

According to the study, low-cost nanoparticles, if immediately injected under the skin close to the site of the bite, can halt or reduce local tissue damage and mitigate the systemic distribution of toxins following venom injection.


Supplements and synthesising


Another group of researchers, led by Matthew Lewin from the California Academy of Sciences in the United States, works on small-molecule therapeutics. The team found out that varespladib, an anti-inflammatory drug, could potentially reduce the required dosage of antivenom and lower treatment costs by improving the performance of imperfectly matched antivenoms.

Since varespladib is already known and has passed clinical trials, it would be quicker to introduce to the market as a supplement treatment for snakebite along with antivenoms, according to a study published last July in the Journal of Tropical Medicine.

“Instead of producing cancer antibodies, we could produce antivenom antibodies.”

Andreas Hourgaard Laustsen, Technical University of Denmark

Scientists are also working on improving existing antivenoms by making them safer and cheaper. Horse-derived antibodies are laborious and expensive to produce, and carry the risk of life-threatening anaphylaxis and serum-sickness — a delayed reaction in which the patient suffers malaria-like symptoms for days.

Some researchers are working to identify and synthesize the toxic proteins in snake venom to bypass the process of breeding snakes to extract venom from them. Fan Hui Wen, a researcher at the Instituto Butantan laboratory in Brazil, says the challenge here is that the ill-effect of snake venom on the human body is not caused by a single toxin, but by a series of molecules that work in synergy. “It’s a soup of toxins,” she says.


A new hope


But the biggest optimism for snakebite treatment lies in monoclonal antibodies. These are human antibodies that have been engineered to bind to the toxins in the snake venom. They can be produced in the lab in the same way as insulin — quick and moderately cheaply.  

“With human antibodies, the antivenom will be safer and will cause no adverse reactions,” explains Andreas Hourgaard Laustsen, a bioengineering professor at the Technical University of Denmark. He notes that this is an expensive area of research in a field that does not interest companies. However, monoclonal antibodies are “low -hanging fruit”, because there is no need to invent new processes, he says.

“Instead of producing cancer antibodies, we could produce antivenom antibodies,” Laustsen says. “We are very lucky to be able to piggyback on fields like cancer, where a lot of antibody work has been done.”

This October, Laustsen reported in Nature Communications on an experimental recombinant antivenom capable of neutralising a toxic component of the venom of the black mamba (Dendroaspis polylepis), one of the most dangerous snake species in Sub-Saharan Africa. But Fan Hui Wen, like Laustsen, warns that snakebite treatment is a field that will not attract business spending without incentives. She sees hope in the fact that the network of laboratories that produce antivenom in Latin America is almost completely owned by local governments. 

In Sub-Saharan Africa and Asia, the costs of treatment are frequently paid by the patients themselves and not by the health system. It means that a cheaper antivenom would have a bigger market as more people would be able to pay for it. “It would create a virtuous cycle,” observes Gutiérrez.

A researcher from the Liverpool School of Tropical Medicine, Nicholas Casewell, proposes that instead of making antivenom for specific snakes, or for a combination of snakes living in a region, it could be possible to make global antivenoms, according to the effect the toxins have on the body.

“We could have one for neurotoxic venom, another for haemorrhage and so on,” he says. “So, you take that diagnostic challenge away from the doctor because instead of trying to guess which snake bit the person, doctors can simply apply the right antivenom based on the symptoms.”
 
This piece was produced by SciDev.Net’s Global desk.

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