Scientists at Seattle’s Fred Hutchinson Cancer Research Center have identified a mini-protein in scorpion venom that can target joint inflammation in arthritic rats — and they’re hoping it can do the same thing for human patients.
It’s too early to say whether the technique will work as well in humans as it does in rats. But the experiments reported today in Science Translational Medicine hold the promise of delivering the benefits of steroid-based therapies for arthritis while avoiding the side effects that come with the use of those steroids.
“For people with multijoint arthritis, the side effects of controlling the disease can be as bad or worse than the disease itself,” Fred Hutch researcher Jim Olson, the study’s senior author, explained in a news release. “Steroids like to go everywhere in the body except where they’re needed most. This is a strategy to improve arthritis relief with minimal systemic side effects.”
The study builds on years of study that Olson has conducted into the compounds contained in scorpion venom. One of those compounds has been found to latch onto cancer cells, providing the foundation for a startup called Blaze Bioscience. Blaze is currently testing a scorpion-derived fluorescent dye called Tumor Paint, which can help surgeons target brain tumors that would otherwise be hard to spot.
After spinning out Blaze in 2010, Olson widened the scope of his search. He and his colleagues screened dozens of mini-proteins known as peptides, looking for compounds that could cross over the blood-brain barrier. They noticed that one of the peptides, known as CDP-11R, tended to accumulate in cartilage. The researchers quickly realized that CDP-11R could be used in a targeted treatment for arthritis.
“It really shows the value of playing scientifically and just doing things for the pure joy of learning,” Olson said. “You never know where it’s going to take you.”
The next step involved pairing the peptide molecule with the right kind of steroid. Eventually, Fred Hutch’s researchers focused on a steroid known as triamcinolone acetonide, or TAA.
When a drug that paired CDP-11R with TAA was injected into rats with arthritis, the peptide-steroid combination gravitated to the joints and eased the rats’ inflammation, as hoped. And if some of the drug leaked into the bloodstream, it became inactive without causing the side effects associated with 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 one of the study’s lead authors, Emily Girard, who’s a staff scientist in Olson’s lab at Fred Hutch. “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.”
The researchers say the technique seems promising enough to move on to human clinical trials, although additional studies with animals will need to be done first. They also suggest that CDP-11R could be used to deliver other types of drugs to a patient’s joints more precisely.
“There is more development to be done,” Girard said, “but I hope that this work results in a therapeutic that will help a lot of people.”
In addition to Girard and Olson, the authors of the study in Science Translational Medicine, “A Potent Peptide-Steroid Conjugate Accumulates in Cartilage and Reverses Arthritis Without Evidence of Systemic Corticosteroid Exposure,” include Michelle Cook Sangar, Gene Hopping, Chunfeng Yin, Fiona Pakiam, Mi-Youn Brusniak, Elizabeth Nguyen, Raymond Ruff, Mesfin Gewe, Kelly Byrnes-Blake (Northwest PK Solutions), Natalie W. Nairn and Dennis M. Miller (Blaze Bioscience), Christopher Mehlin, Andrew Strand, Andrew Mhyre, Colin Correnti, Roland Strong and Julian Simon.
The research was supported by the National Cancer Institute, Blaze Bioscience and philanthropic funding from Project Violet, the Wissner-Slivka Foundation, the Kismet Foundation, the Sarah M. Hughes Foundation, Strong4Sam, Yahn Bernier and Beth McCaw, Len and Norma Klorfine, Anne Croco and Pocket Full of Hope. The work was performed in collaboration with Blaze Bioscience, which has an ongoing collaboration and option agreement with Fred Hutch to develop optimized peptide therapeutics.
Competing interests: Olson is a founder and shareholder of Blaze Bioscience, which retains intellectual property rights to the peptides used in this research.
