CRISPR

Relief

CRISPR could be the end of opioid abuse

After success in mice, CRISPR could be used to treat chronic pain in the future.

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Suffering from chronic pain can be both a debilitating and lonely experience.

Often unaccompanied by outside markers of distress, an actual diagnosis — whether it be lingering pain from an old injury, procedure, or a more elusive condition like fibromyalgia — can be difficult to come by. There are also few reliable treatments beyond opioid painkillers, which can be highly addictive.

But in a new study, researchers say there may soon be a new treatment on the market to treat this pain thanks to the famous gene-editing toolkitCRISPR-Cas9. This technology could allow patients to side-step the need for opioids altogether.

Tony Yaksh, a lead author on the study and professor of anesthesiology and pharmacology at UC San Diego, tells Inverse that such a treatment in humans is at least four to eight years away.

The research was published Wednesday in the journal Science Translational Medicine.

Why it matters — So far, this gene-editing approach to chronic pain has only been successfully trialed in mice.

But if proven successful in humans it could be a huge step toward drastically lessening the use of opioids for pain relief. This could have huge implications for communities rocked by the havoc caused by this addictive drug.

Here’s the background — Chronic pain, which is classified as a pain that lasts for 3 months or more, affects between 19 to 50 percent of the world population. Despite its prevalence, it remains a difficult diagnosis to treat well.

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

This is due in part to the complexity of the nerve network that transmits the experience of pain between your body and your mind.

Instead of blocking pain from being experienced (as opioids do by binding to opioid receptors on nerve cells and dampening their pain transmission), the team behind this new study decided to investigate whether they could genetically toggle off this pain transmission altogether.

By carefully changing parts of our genetic code, researchers now believe CRISPR could be an addiction-free solution to chronic pain.Shutterstock

In particular, they were interested in one particular ion channel responsible for transmitting pain signals called NaV 1.7. This ion channel, when not working properly, has previously been connected to a rare genetic disorder called congenital insensitivity to pain (similar to the condition of the 71-old-Scottish woman who lived her whole life pain free.)

Essentially, the team wanted to see if they could jump-start this genetic mutation in those with chronic pain.

What they did — Before jumping straight to humans, the team first had to try their gene-editing approach in lab mice. The mice in this study were bred to display different types of chronic pain, including one induced by chemotherapy, which is becoming increasingly common in humans.

To achieve these targeted genetic mutations, the team designed a platform called LATER which combined “dead” CRISPR Cas9 proteins (so that the mutation would remain reversible) with zinc finger gene editing (another type of targetted gene editing designed to zero in one specific DNA sequences).

With this genetic concoction mixed up, the team then injected it into the spinal cords of the mice.

The authors report that the mice showed no negative side-effects following their genetic cocktail and demonstrated sustained pain relief (as tested by inducing inflammation on their hind paws) for between 15 to 44 weeks.

What’s next — While Yaksh says that while it will be four to eight years before this treatment can be used on humans, when that time comes, it could be an extremely effective treatment when used in conjunction with other pain relief methods.

The researchers used CRISPR and zinc fingers to repress NaV 1.7 and block pain signals in neurons in mice.Credit: A.M. Moreno et al., Science Translational Medicine (2021)

“In managing any chronic pain state, the driving concern is to solve the problem with the least invasive intervention,” Yaksh tells Inverse. Non-invasive treatments include physical therapy, mindfulness, and topical medication.

However, when a person doesn’t respond well to these interventions, that could be where this new treatment comes in — rather than continuing to medicate.

“When the pain pathology is not responsive to lesser interventions, when it is persistent, and its etiology is consistent with a role for the NaV1. 7 target, we see this as the therapeutic space for this targeted intervention,” Yaksh says.

While it an extreme intervention, compared to simply taking a pill, it's still a reasonable alternative to daily pills when the addictive nature of opiates is taken into consideration, Yaksh says.

He also says that research suggests such a treatment could be implemented across the age spectrum, from pediatrics to geriatrics. Currently, Yaksh says that such a treatment might be most compatible with chronic pain stemming from inflammation (such as arthritis) and nerve injuries.

Abstract: Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)–dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. 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.
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