CRISPR Could Switch Off Chronic Pain Without Opioids
In2006, scientists described the curious case of a Pakistani boy who seemed resistant 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 leap 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 all of them harbored mutations during a gene called SCN9A. Two other families in northern Pakistan were found to possess similar mutations that made them unable to feel pain.
Now, a biotech startup wants to mimic this mutation to treat people with chronic pain. during 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 consequences 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 medicine that alters the brain’s perception of pain. An estimated 20% of U.S. adults suffer from chronic pain, consistent with the Centers for Disease Control and Prevention, and lots of are prescribed powerful opioids to assist them to cope. In recent years, there’s been a push by pharma to seek out non-addictive pain therapies.
“There’s an enormous opioid epidemic within us, and there’s really nothing working for these patients,” Ana Moreno, Ph.D., CEO of Navega Therapeutics and first author on the study, tells Future Human. Moreno founded the corporate in 2018 alongside co-author Prashant Mali, Ph.D., a bioengineering professor at the University of California, San Diego, when she was still a doctoral student in his lab.
“The problem is, we'd like the pain to measure. Pain is an alarm that something is wrong.”
As a student, Moreno first began exploring the utilization 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 ordering. Instead, it uses a modified sort of CRISPR to bind to a gene — during this case, SCN9A — and block its expression.
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The SCN9A gene provides instructions for creating a “sodium channel” found in nerve cells that transmits pain signals to the brain. The channel, referred to as Nav1.7, acts as a volume knob for pain. When it’s turned too high, it sends many pain signals. When it’s too low, it doesn’t send pain signals. Certain rare mutations, just like the ones found within 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 are curious about creating drugs to focus on this channel.
“All the drug companies went bananas and that they tried to form blockers of the channel, and really none of them worked alright, if at all,” says John Wood, Ph.D., a neurobiologist at University College London who has studied the SCN9A gene extensively but isn’t involved within the new paper. His group found that once they deleted the gene in mice entirely, it eliminated pain in mice. “The insight from mice was that you simply need to completely block all the activity of this channel.”
Traditional drugs can’t do this, especially for long periods of your time, Wood says. But permanently deleting a gene in people would be a risky approach.
“The problem is, we'd like the pain to measure,” says Rajesh Khanna, Ph.D., a pharmacology professor and chronic pain researcher at the University of Arizona who wasn’t involved in the Navega Therapeutics study. “Pain is an alarm that something is wrong.”
For that reason, the corporate doesn’t aim to eliminate pain. within the study, it appeared to diminish pain in mice. Animals that received a spinal injection of the therapy were slower to tug faraway from being exposed to painful heat, cold, or pressure and spent less time licking or shaking after being hurt.
There are still tons left to find out before such a therapy might be used widely. For one, the Nav1.7 channel is additionally present in sensory neurons within 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'll be challenges to commercializing the approach. Gene therapies are incredibly expensive to manufacture and may cost patients many thousands of dollars.
It’s also unknown whether patients might be given a second injection. The therapy uses a kind 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 system should recognize it as foreign and make antibodies against it. If an individual were to urge 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 skill long the consequences of the CRISPR therapy will last in people, but they predict it might be several months up to a couple of years. It lasted 44 weeks in mice with inflammatory pain and 15 weeks in those with chemotherapy-induced pain. Over that period of your time, the treated mice didn’t show signs of increased pain sensitivity or changes in normal motor function, which may happen with the continual use of opioids.
Moreno thinks the danger of addiction to CRISPR therapy is low since it works differently than opioids, which alter the way we perceive pain by working on neurotransmitters — chemical messengers released by the neurons within the brain.
Researchers decided to test the therapy in monkeys next and hope to start human clinical trials during a few years.
Because of the value and novelty of the approach, Wood says it might be a short time before it’s accepted as a mainstream therapy. “But if it had been cheap and side-effect-free, it’d be great for vast numbers of individuals .”
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