How a Century-Old Drug Could Revolutionize Cobra Bite Treatment

About 1.8 million people worldwide are bitten by snakes each year. Of those, up to 138,000 die, and another 400,000 suffer from permanent scarring and disability.

Many cobras have tissue-damaging venoms that current antivenoms can’t treat. We have discovered that cheap, readily available blood-thinning medications can be repurposed as antidotes for these venoms. Using CRISPR gene-editing technology, we learned how these venoms attack our cells and found that a common class of drugs called heparinoids can protect tissue from the venom. Our research is published today in Science Translational Medicine.

Snakebites: A Serious Problem

Snake venoms consist of many different compounds targeting the heart, nervous system, or tissue at the exposure site (such as skin and muscle). Much snakebite research focuses on the most deadly venoms, leaving less deadly but still harmful venoms—such as those from cobras—less studied.

In regions where cobras live, serious snakebites can lead to devastating effects, such as amputation, life-changing injuries, and loss of livelihood. The World Health Organization has declared snakebite a “Category A” neglected tropical disease and aims to reduce the burden of snakebites by half by 2030.

The Limitations of Current Treatments

The only current treatments for snakebites are antivenoms, made by exposing non-human animals to small amounts of venom and harvesting the antibodies they produce. Antivenoms save lives but have several drawbacks: they are species-specific, expensive, require cold storage, and must be administered via injection in a hospital. Moreover, antivenoms can’t prevent local tissue damage, as the antibodies are too large to reach peripheral tissue, such as a limb.

Understanding Cobra Venom

Our team, from the University of Sydney, the Liverpool School of Tropical Medicine, and Instituto Clodomiro Picado, aimed to find alternative treatments for snakebites. We started with cobras, using venom from the African spitting cobra, which is known to cause tissue damage. We performed a whole genome CRISPR screen, disabling a different gene in each cell, and exposed them to the venom. Cells that survived were missing the elements the venom needed to cause harm, allowing us to identify these critical features.

We discovered that various cobra venoms need particular enzymes to kill human cells. These enzymes make long sugar molecules called heparan and heparin sulfate, which are found on the surface of human and animal cells. Snake venoms have evolved to exploit these common molecules to cause damage.

How Heparin Decoys Reduce Tissue Damage

Heparin has been used as a blood-thinning medication for almost 100 years. We tested this drug on human cells to see if flooding the system with free heparin could serve as a decoy target for the venom. Remarkably, this worked, and the venoms no longer caused cell death, even when heparin was added after the venom. We also tested heparin against venoms from Asian cobras with similar protective effects. Injecting a smaller synthetic version of heparin, called tinzaparin, reduced tissue damage in mice with an artificial “snakebite.”

We found that heparin inhibits “cytotoxic three-finger toxins,” a major cause of tissue injury. Until now, no drugs were known to work against these toxins. The next step will be to test the effects of heparin in people.

Cheaper, More Accessible Snakebite Treatment

Our goal is to develop a snakebite treatment device containing heparin-like drugs called heparinoids, similar to EpiPen adrenaline injectors used for severe allergic reactions. These devices could be distributed to people at high risk of cobra bites.

Heparinoids are already inexpensive essential medicines used to prevent blood clots. The US Food and Drug Administration has approved them for self-administration in humans, which may reduce the time required for bringing this treatment to market. Heparinoids are also stable at room temperature, making them more accessible in remote regions and deliverable faster in the field.

Other studies have confirmed the usefulness of repurposing drugs for treating snakebites. These drug combinations could herald a new age for snake venom treatment that doesn’t solely rely on costly antivenoms.

Our lab has previously used CRISPR screening to investigate box jellyfish venom, and we are currently studying other venoms, from bluebottles to black snakes. Our screening technique uncovers a wealth of information about venom, feeding into the larger goal of creating universal and broad-acting venom antidotes.