Can Cone Snail Venom Be the Next Treatment for Neuropathic Pain?
Interview with J. Michael McIntosh, MD
Researchers may have a new mechanism for treating neuropathic pain, and the key ingredient comes from a particular venomous sea snail. The Conus Regius, or “crown cone,” can be found in the Caribbean and Gulf of Mexico and is known for using its paralyzing venom to attack prey.
“One of the primary systems the crown cone snail targets is the neuromuscular junction that contains nicotinic acetylcholine receptors,” J. Michael McIntosh, MD, told Practical Pain Management. Nicotinic acetylcholine receptors (nAChRs) are found on skeletal muscles and enable muscular contraction.
The research team led by Dr. McIntosh, who is professor of psychiatry at the University of Utah and a medical director at the Veterans Hospital in Salt Lake City, Utah, have used this venom to develop an analog compound that already shows promise as a treatment for chemotherapy-induced neuropathy, according to a recently published study in Proc Natl Acad Sci.1
Interestingly, an entirely different compound from a different species of cone snail was previously developed for human use. Ziconotide (Prialt), which was approved by the US Food and Drug Administration (FDA) in 2004, is an intrathecal analgesic for the treatment of severe chronic pain.2
The challenge of developing an analog for neuropathic pain comes from the fact that typical prey for cone snails, like fish, worms, and other mollusks, don’t have the same types of nicotinic receptors as humans. So researchers have had to engineer compounds that target the receptors found in human tissue, something Dr. McIntosh and his colleagues believe they now have achieved.
From Paralytic to Analgesic: Engineering the Cone Snail Venom
For years, researchers were interested in a type of peptide found in the cone snail toxin called Vc1.1, which showed analgesic effects on neuropathic pain and even appeared to accelerate the recovery of functional neurons.3-5
Vc1.1 was not successful in Phase II human clinical trials, likely due to the compound not being potent for the human receptors. However, the research pointed to a specific treatment target, α9α10 nAChRs.
“Then we looked for other compounds that targeted this same receptor with the idea being, if this is truly the mechanism of action, then we should be able to find other peptides that act by the same mechanism and they should also be analgesic,” Dr. McIntosh explained.
This led Dr. McIntosh and his colleagues to another compound found in the Conus regius’s venom, α-conotoxin RgIA, which they were able to engineer into an analog called RgAI4. “Basically, we made modifications to the compound that was found in the cone snail venom to not only maintain the favorable properties but also to make it potent for the human-type receptors,” Dr. McIntosh told Practical Pain Management.
A New Treatment for Neuropathic Pain?
Dr. McIntosh and his colleagues then tested the compound in rats that had been given oxaliplatin, a first-line chemotherapeutic agent, in order to create a model for chemotherapy-induced neuropathic pain.6
When these rats were administered RgIA4 (0.128–80 μg/kg), the compound appeared to prevent any mechanical hypersensitivity in the rats from 30 minutes to 24 hours after administration. For 21 days, the researchers administered RgIA4 (100 μg/kg) daily and found no behavioral, neurological, or autonomic effects. The same was true for rats that had been given a single 5 mg/kg dose of RgIA4.
Further tests also showed that mice without the α9 type of nAChR did not develop chronic cold allodynia when given oxaliplatin. Indeed, when these mice were given RgIA4 later on, it did not have a significant effect, noted the investigators.
Dr. McIntosh and his colleagues have teamed up with the biotech company Kineta, Inc. to continue preclinical testing to enable filing for an investigational new drug status with the FDA.
One caveat: the drug would not be in pill form, since the gastric enzymes in a person's body would break down the peptide of action. A similar problem is found with ziconotide, which needs to be infused into the intrathecal space in order for it to be effective.
Unlike ziconotide, RgIA4 does not need to be given intrathecally. “We believe the RgAI4 is acting in the periphery, and so it can be given by subcutaneous injections,” Dr. McIntosh noted.
The drug also may become a viable treatment option for other kinds of neuropathy, such as diabetic neuropathy and nerve trauma-related neuropathy. “We find that if you treat with this medication, it alters the pathophysiology, so you see less loss of nerve fibers, less loss of myelin, you see less glia in the spinal cord—there seems to be an actual modification of the disease course,” said Dr. McIntosh.
While there is still much research to be done in this area, Dr. McIntosh believes this compound could become a bright example of how researchers can derive new compounds found natural sources. “Things like the cone snails, and natural products in particular, can sometimes help point us in the right directions that we were previously unaware of, and open horizons,” he concluded.
This research was supported by grants from the National Institutes of Health, a grant from the Department of Defense, and a sponsored-research agreement from Kineta, Inc. The α-Conotoxins, including the α-conotoxins referenced in the study, have been patented by the University of Utah, with Dr. McIntosh and study co-author Baldomero M. Olivera, PhD, listed as inventors. No other conflicts of interest have been reported.