Could gene editing help us fight chronic pain?

A CRISPR-based technique as an alternative to opioids is making news. The unlikely approach could help millions and help reduce America’s dependence on opioids, according to several new studies.

Image credits: K State Research.

For now, a current standard of care for chronic pain often involves opioids, and this has become quite a problem, as opioids pose the risk of getting addicted to them. It is ironic: the very mitigant designed to ease suffering has turned out to be in an of itself a “crisis.”

Over the past two decades, there has been a sharp rise in the use of prescription opioids in the US, with Americans consuming around 80% of the world’s strongest opioids. Researchers are also taking note of this and they’re looking for ways to offer effective pain management in a world without opioids. Now, they’re finally starting to report some good results.

The Consortium Against the overuse of Opioids in Surgery (CAOS) was established in August 2019 with the aim of reducing harmful effects from opioid use among surgical patients. CAOS wanted to inform opioid prescribing policy and to improve clinical practice via collaborative research. Members included professors and experts in fields such as molecular biology, anesthesiology, orthopaedics, and epidemiology research.

A forceful and multidisciplinary call from experts associated with CAOS came out in Frontiers in Surgery last year. “The Surgeon’s Role in the Opioid Crisis: A Narrative Review and Call to Action” called for specific action, with the authors emphasizing “a pressing need to optimize postoperative prescribing practices.”

This month, those focused on an alternative to opioids for pain will want to check out a new study published on March 10 in Science Translational Medicine. The study authors from the University of California San Diego, admit they are working on an area which has thus far delivered limited returns. But things are about to change, they say.

“Despite decades of research, the goal of achieving broadly effective, long-lasting, nonaddictive therapeutics for chronic pain has remained elusive,” the study writes.

The developed an approach they call LATER, which stands for “long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7” — an important channel in the transmission of pain. Their work is particularly promising since LATER reversed chemotherapy-induced chronic pain in mice, and may be effective for treating chronic pain of multiple origins.

A direct hit at Nav1.7

In a study published in Nature, researchers reported that they might be able to stop pain signals traveling to the brain by preventing neurons from producing Nav1.7. With CRISPR’s edge in targeting genes with precision, the researchers thought they might be able to hit Nav1.7 directly, without any “off-target” effects. In an article discussing the study for Nature, journalist Ariana Remmel notes that “mice that received doses of chemotherapy became very sensitive to pain, but lost that sensitivity after a single injection of the gene therapy.” This is an approach that represses, at least temporarily, a gene involved in sending pain, but it could last for months.

For pain sufferers and medical professionals who treat them, duration is clearly an important part of the problem. The treatment was tested at various timepoints, said the news release, and was still effective after 44 weeks in the mice with inflammatory pain– and 15 weeks in those with chemotherapy-induced pain.

Quoted in Nature, a Yale neuroscientist weighed in on information that the pain relief seemed to last, in some cases, for as long as 44 weeks after the injection. “That’s quite remarkable,” comments Sulayman Dib-Hajj at Yale, and it’s hard to disagree.

The authors of the study summed up their results thusly:

“Our results show effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states.”

NaV1.7 was also the focal point of a study led by Ana Moreno from the University of California, San Diego. Moreno recals the time she came across a paper about a genetic mutation that caused humans to feel no pain.

“This mutation inactivates a protein in pain-transmitting neurons in the spinal cord, called NaV1.7. In individuals lacking functional NaV1.7, sensations like touching something hot or sharp do not register as pain. On the other hand, a gene mutation that leads to overexpression of NaV1.7 causes individuals to feel more pain.”

Click. Moreno thought, “By targeting this gene, we could alter the pain phenotype,” she said in the UCSD news release. “What’s also cool is that this gene is only involved in pain. There aren’t any severe side effects observed with this mutation.”

So it seems to add up, and a non-opioid way to deal with pain may be just around the corner.

What’s next? The length of duration is still being tested, researchers said. Hopefully, it will be long-lasting.

*The initial version of this article was edited as it wrongly stated that a Nature study was led by Ariana Remmel, when in fact, Remmel was a journalist covering the study.

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