Reengineering Life is a column from Future Human about the ways humans are using biology to reprogram our bodies and the world around us.
In 2006, scientists described the curious case of a Pakistani boy who seemed immune to pain. The 10-year-old street performer amazed audiences by walking on burning coals and stabbing himself with knives without flinching.
His resistance to pain later led him to jump off a building to impress his friends. Tragically, he died from the resulting injuries. He had just turned 14.
Several of the boy’s relatives had never experienced pain either. When researchers collected samples of their blood and analyzed their genes, they found that they all harbored mutations in a gene called SCN9A. Two other families in northern Pakistan were found to have similar mutations that made them unable to feel pain.
Now, a biotech startup wants to mimic this mutation to treat people with chronic pain. In a new paper published March 10 in Science Translational Medicine, researchers used the gene-editing technique CRISPR to successfully repress the gene and increase pain tolerance in mice. The effects lasted up to 44 weeks. If it proves safe in people, the therapy could offer an alternative to opioids, the authors say.
Opioids are a highly addictive class of drugs that alter the brain’s perception of pain. An estimated 20% of U.S. adults suffer from chronic pain, according to the Centers for Disease Control and Prevention, and many are prescribed powerful opioids to help them cope. In recent years, there’s been a push by pharma to find nonaddictive pain therapies.
“There’s a huge opioid epidemic in the United States, and there’s really nothing working for these patients,” Ana Moreno, PhD, CEO of Navega Therapeutics and first author on the study, tells Future Human. Moreno founded the company in 2018 along with co-author Prashant Mali, PhD, a bioengineering professor at the University of California, San Diego, when she was still a doctoral student in his lab.
“The problem is, we need pain to live. Pain serves as a warning signal that something is wrong.”
As a student, Moreno first began exploring the use of CRISPR for pain. CRISPR is best known for its ability to delete a gene, but the treatment that Navega Therapeutics is developing doesn’t make a permanent change to a person’s genetic code. Instead, it uses a modified form of CRISPR to bind to a gene — in this case, SCN9A — and block its expression.
The SCN9A gene provides instructions for making a “sodium channel” found in nerve cells that transmits pain signals to the brain. The channel, known as Nav1.7, acts like a volume knob for pain. When it’s turned too high, it sends lots of pain signals. When it’s too low, it doesn’t send pain signals. Certain rare mutations, like the ones found in the Pakistani families, have the latter effect, while other mutations cause people to be more sensitive to pain.
Ever since scientists discovered its association with pain, drug developers have been interested in creating drugs to target this channel.
“All the drug companies went bananas and they tried to make blockers of the channel, and really none of them worked very well, if at all,” says John Wood, PhD, a neurobiologist at University College London who has studied the SCN9A gene extensively but isn’t involved in the new paper. His group found that when they deleted the gene in mice entirely, it eliminated pain in mice. “The insight from mice was that you have to completely block all the activity of this channel.”
Traditional drugs can’t do that, especially for long periods of time, Wood says. But permanently deleting a gene in people would be a risky approach.
“The problem is, we need pain to live,” says Rajesh Khanna, PhD, a pharmacology professor and chronic pain researcher at the University of Arizona who wasn’t involved in the Navega Therapeutics study. “Pain serves as a warning signal that something is wrong.”
For that reason, the company doesn’t aim to eliminate pain entirely. In the study, it seemed to diminish pain in mice. Animals that received a spinal injection of the therapy were slower to pull away from being exposed to painful heat, cold, or pressure and spent less time licking or shaking after being hurt.
There’s still a lot left to learn before such a therapy could be used widely. For one, the Nav1.7 channel is also present in sensory neurons in the nose, so Khanna says one potential side effect of the therapy is that it could dull a person’s sense of smell.
Wood says the study is “intellectually very exciting,” but adds that there will be challenges to commercializing the approach. Gene therapies are incredibly expensive to manufacture and can cost patients hundreds of thousands of dollars.
It’s also unknown whether patients could be given a second injection. The therapy uses a type of engineered virus called an adenovirus to deliver the CRISPR machinery to cells. The virus is engineered so that it can’t cause infection, but the immune system may still recognize it as foreign and make antibodies against it. If a person were to get a second dose of the gene therapy later on, those antibodies could attack it and render the treatment ineffective.
Moreno and her team don’t yet know how long the effects of the CRISPR therapy will last in people, but they predict it could be several months up to a few years. It lasted 44 weeks in mice with inflammatory pain and 15 weeks in those with chemotherapy-induced pain. Over that period of time, the treated mice didn’t show signs of increased pain sensitivity or changes in normal motor function, which can happen with continuous use of opioids.
Moreno thinks the risk of addiction to the CRISPR therapy is low since it works differently than opioids, which alter the way we perceive pain by acting on neurotransmitters — chemical messengers released by the neurons in the brain.
Researchers plan to test the therapy in monkeys next and hope to begin human clinical trials in a few years.
Because of the cost and novelty of the approach, Wood says it could be a while before it’s accepted as a mainstream therapy. “But if it was cheap and side-effect free, it’d be great for vast numbers of people.”