Proteins From Scorpion Venom Deliver Arthritis Drugs to Joints

A new study published in Science Translational Medicine outlines research in which scientists have repurposed scorpion venom to concentrate arthritis drugs in the joints of rats. This approach overcomes the issue of systemic toxicity that is associated with conventional therapeutics.

"Steroids like to go everywhere in the body except where they're needed most"

The lives of many individuals across the globe are adversely impacted by arthritic diseases, whether that be through the suffering of pain or due to limited mobility. Whilst there are symptomatic therapeutics available for such conditions, for example steroids, these drugs are often limited by off-tissue toxicity that can cause serious side effects and limits their systemic use.

"For people with multi-joint arthritis, the side effects of controlling the disease can be as bad or worse than the disease itself," said Dr Jim Olson from the Clinical Research Division at Fred Hutch. He added: "Steroids like to go everywhere in the body except where they're needed most."

Olson adopts an approach to developing novel therapeutic strategies that could be considered slightly unconventional, using nature as a blueprint.

He is the senior scientist on a recent project in which a series of mini proteins known as cystine-dense peptides (CDPs) have been discovered and used to deliver drugs directly to the cartilage after systemic administration in rodents.

Scorpion venom: A source of CDPs

Where do these mini proteins come from, you ask? Well, they're frequently found in the venom of snakes, spiders and scorpions as part of their biodefence mechanism. They can also sometimes be found in bacteria, fungi, molluscs and other species.

Olson's latest publication is a result of many years of work exploring what he calls "optides", short for "optimized peptides" – very small proteins that are obtained from natural organisms.

"My thought was that these peptides that are in venoms or toxins might have really unique biodistribution in human bodies," he said. "If something is using them for predation, they need to get to certain places rapidly."

After discovering the mini-protein, Olson collaborated with scientists in Fred Hutch's Molecular Design and Therapeutics core facility to develop novel ways to utilize it therapeutically and link it to drugs.

Eventually, they conjugated the mini-protein with a steroid called Triamcinolone acetonide, or TAA for short, using a labile chemical linker. They found that systemic administration of this novel construct reversed inflammation in the joints of a collagen-induced rat model of rheumatoid arthritis. Once TAA enters the bloodstream it becomes inactive, reducing the systemic side effects that are often observed in arthritic patients taking steroids.

"It's a pretty simple idea to take a mini-protein that naturally goes to cartilage and attach something to it so that you get targeted delivery of the drug, but it was challenging to accomplish," said Emily Girard, staff scientists in Olson's research laboratory and one of the study's lead authors.

She continued: "We had to learn and adapt the behavior of the mini-protein, the chemical linker and the steroid payload to make a product that would go to cartilage, stay as long as we needed it to, release the drug at the right rate, and have a local but not systemic effect. There is more development to be done, but I hope that this work results in a therapeutic that will help a lot of people."

Beyond controlling arthritis

The scientists hope that they can test the novel approach in patients through a human clinical trial eventually, but first they are required to further understand any potential unknowns relating to toxicology.

The scientists are also optimistic that the mini-proteins could potentially be utilized to deliver other drugs into cartilage. Olson commented: "We think that steroids have important potential as a candidate for clinical development and we're actively exploring other payloads that could be delivered to the joints." He concluded: "The long-term goal is to deliver molecules that go beyond controlling arthritis to actually reversing it."

Reference: Cook-Sangar et al. (2020). A potent peptide-steroid conjugate accumulates in cartilage and reverses arthritis without evidence of systemic corticosteroid exposure. Science Translational Medicine. https://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aay1041.