SiteOne Uses Natural Toxins to Alleviate Debilitating Pain

Chronic pain afflicts more than 100 million people in the United States, which makes pain alleviation one of the greatest unmet medical challenges. SiteOne Therapeutics, located in the UCSF QB3 incubator, thinks it has a solution. SiteOne believes that the best way to treat chronic pain is to block pain signals before they reach the brain. It is developing a highly modified natural marine toxin found in snail venom to block these signals.

“At SiteOne we are trying to make new and better sodium channel blockers for pain relief and diagnosing pain,” said co-founder George Miljanich.

As a postdoctoral fellow under UCSF emeritus professor Reg Kelly, Miljanich worked on developing a model system to understand calcium-dependent neurotransmitter release. Along the way, he realized that the same snail venom he used to block voltage-gated calcium channels could be developed into a potent analgesic. Not long after Miljanich took on a neurobiology professorship at USC, this discovery kindled his first startup, Nurex, where he led the development of Prialt, the first non-opioid and non-NSAID pain therapy on the market.

After Nurex was acquired by Elan Pharmaceuticals in 1998, Miljanich began focusing on sodium channels. Two key studies linking sensory pain to genetic mutations in the gene encoding the Nav1.7 sodium channel established this channel's importance in the pain-sensing pathway. In 2004, the Journal of Medical Genetics published a study detailing individuals with mutated channels who experienced intense pain with very mild stimuli such as mildly warm water. A few years later, a study out of the University of Cambridge identified two Pakistani families with loss-of-function mutations that had the opposite effect, resulting in very little pain perception regardless of the stimuli.

Stanford researchers and SiteOne co-founders Justin Du Bois and John Mulcahy synthesized the first selective sodium channel inhibitors based on the marine neurotoxin, saxitoxin.

Miljanich conceded that one of their biggest challenges in developing therapeutics from saxitoxins is that these neurotoxins are not specific. They shut down all voltage-gated sodium channels indiscriminately. However, Milanich said they have identified a two amino acid variant in the mouth of the channel that allows them to develop very potent and specific Nav1.7 blockers.

Du Bois also teamed up with Stanford radiologists Sandip Biswal and Frederick T. Chin to develop fluorescent labeled saxitoxin for PET (positron emission tomography) imaging with the hopes of developing the first diagnostic tool to visualize pain.

"If we can localize neurons causing the pain, we can intelligently guide pain physicians in terms of treatment, pharmacology, surgery, physical therapy and electric stimulation," said Miljanich.

With more than 24 patents, 50 publications and a numerous industry awards, Miljanich certainly has deep experience in commercializing ion channel biology. Still, he credits his work with all three partners of the QB3 family—UCB, UCSC and UCSF—for laying the foundation of his current work at SiteOne and providing a collegial space that meets startup needs.

“The UCSF QB3 incubator has been key in our success. [Before QB3], we were in this traditional building, and we were paying for space we didn’t use.” Miljanich held his arms out wide and quickly swung them close together as he said, “Here, we can expand or contract as we need.”