Gene-silencing injection reverses pain in mice – Science Magazine

An experimental pain treatment tested in mice targets ion channels on sensory nerves, shown above in the human spinal cord.

By Kelly ServickMar. 10, 2021 , 2:00 PM

Swallowing an oxycodonepill might quiet nerves and blunt pain, but the drug makes other unwanted visits in the brainto centers that can drive addiction and suppress breathing. Now, a study in mice shows certain types of pain can be prevented or reversed without apparent side effects by silencing a gene involved in pain signaling. If the approach weathers further testing, it could give chronic pain patients a safer and longer lasting option than opioids.

Its a beautiful piece of work, says Rajesh Khanna, a neuroscientist who studies pain mechanisms and potential treatments at the University of Arizona. Despite successes of gene therapy against rare and life-threatening disorders, few teams have explored genetic approaches to treating pain, he says. Thats in part because of reluctance to permanently change the genome to address conditions that, although disabling, arent always permanent or fatal. But the new approach doesnt alter the DNA sequence itself and is theoretically reversible, Khanna notes. I think this study is going to be our benchmark.

A prick of the finger or a punch in the gut causes pain because nerves branching through our bodies reach into the spinal cord to relay messages to the brain. Those messages can persist even after the initial injury has healed, causing chronic pain.

To fire their electrical signals, pain-sensing nerves rely on the flow of ions across protein channels in their membranes. One such channel, called Nav1.7, stands out for the remarkable pain disorders that arise when it malfunctions. People with genetic mutations that make Nav1.7 overactive are prone to attacks of burning pain. Those with mutations that deactivate Nav1.7 feel no pain at all.

In textbooks, you can find these horrible pictures of children without fingers and with only half a nose, because they didnt notice when they injured themselves, says Claudia Sommer, a neurologist at the University of Wrzburg.

Nav1.7 is an obvious target for pain drugs but blocking the channel itself has proved tricky. Several early drug candidates failed in clinical trials. One major challenge is finding a drug that binds to Nav1.7 while avoiding similar channels in the Nav family that are important to the nervous system, heart, and other organs.

In the new study, researchers instead aimed to reduce the amount of Nav1.7 that cells make in the first place. Bioengineer Ana Moreno and her colleagues at the University of California, San Diego, modified the molecular scissors of the gene editor CRISPR. Changes to the cutting enzyme Cas9 caused it to bind to DNA that makes Nav1.7 without slicing it, effectively preventing the Nav1.7 protein from being made. The researchers enhanced this silencing effect by hitching Cas9 to a repressor, another protein that inhibits gene expression.

The researchers tested the Cas9 approachand a similar approach using another gene-editing protein known as a zinc fingerin mice given the chemotherapy drug paclitaxel, which can cause chronic nerve pain in cancer patients. The team measured pain by poking the animals paws with a thin nylon filament. Paclitaxel prompted mice to withdraw from gentler pokes, indicating that a normally nonpainful stimulus had become painful. But 1 month after an injection of the gene-silencing treatment into their spinal fluid, rodents responded much like mice that had never gotten paclitaxel, whereas untreated rodents remained hypersensitive, the team reports today in Science Translational Medicine.

The approach could also prevent pain when given before paw injections of either the inflammation-causing compound carrageenan or a molecule called BzATP that increases pain sensitivity. And treated mice behaved no differently from untreated ones when their opposite pawnot inflamed by carrageenanwas exposed to a hot surface. Thats an encouraging initial sign that the injection didnt silence Nav1.7 so completely that it creates a dangerous numbness to all pain, Moreno says. Behavioral tests so far havent turned up evidence of potentially concerning side effects; the injections didnt appear to alter the animals movement, cognition, or anxiety levels.

Its not yet clear how long the effects of an injection last, Moreno says; her team studied the carrageenan-exposed mice up to 10 months after treatment and still saw effects. But she expects that changes in the epigenomethe chemical compounds that stud DNA and regulate gene expressionmight naturally reverse the effects of the gene-silencing proteins over time.

The approach is superclever, says Holly Kordasiewicz, head of neurology at Ionis Pharmaceuticals. The company is developing pain treatments to block production of Nav1.7 using genetic strands called antisense oligonucleotides, the effects of which Kordasiewicz says would likely be shorter in duration than the gene-silencing approach.

Still, cost could prevent a genetic strategy from becoming a treatment for a condition as common as chronic pain, cautions neurobiologist John Wood of University College London. Gene therapy is really very appealing intellectually, he says, but its so expensive to manufacture the therapiesin particular the viruses that deliver genetic material to cellsthat many companies are reluctant to invest in it.

Moreno expects an eventual gene-silencing treatment for pain to work at lower doses (and costs) than gene therapies already in the clinic, in part because it would be precisely delivered to target cells via a spinal injection rather than circulating in the bloodstream.

She and her collaborators have also founded a company, Navega Therapeutics, to develop their approach. They will begin by trying to treat inheritederythromelalgia, a rare genetic pain disorder caused by overactive Nav1.7. Eventually, Moreno hopes the approach can treat more common types of chronic pain, including nerve pain caused by chemotherapy and diabetes. The company is now preparing for a crucial next step in the research: tests in nonhuman primates.

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Gene-silencing injection reverses pain in mice - Science Magazine