Pain signals are transmitted by the neurons from the spinal cord to the brain.Credit: Jose Calvo / Science Photo Library
According to a study, a no-silence technique based on CRISPR can relieve pain in mice1. Although the therapy has long been unused in humans, scientists say it is a promising approach to chronic pain that lasts for months or years. Chronic pain is usually treated with opioids such as morphine, which can lead to addiction.
“It’s a big challenge that the best medicine we have to treat pain gives us another disease,” said Margarita Calvo, a pain doctor at the Pontifical Catholic University of Chile in Santiago, who was not involved in the research. was not. That’s why the CRISPR-based technique is exciting, she says.
Scientists are already evaluating CRISPR therapies that modify a person’s genome as treatments for blood diseases and some forms of hereditary blindness. The new version of CRISPR does not modify genes directly – it can prevent them from being expressed – and so they should not cause permanent changes, although it is unclear how long their effects will last.
A new way to target pain
Some studies estimate that a large proportion of the population in Europe and the United States – up to 50% – experience chronic pain2,3. This pain can become debilitating over time by limiting someone’s activity and negatively affecting their mental health. Despite the prevalence of the condition, there are few options to provide long-term relief without side effects. Nevertheless, doctors took away from prescribing opioids due to the risk of addiction, and this further limited their options.
This fate inspired bioengineer Ana Moreno and colleagues at the University of California, San Diego to seek an alternative treatment.
Pain registers in the brain when a stimulus – such as touching a hot pan or being stabbed with a sharp object – causes neurons to send an electrical signal through the nerves in the spinal cord and upward to the brain. This happens when pore-like openings along the neuron – called ion channels – become open and close to allow ions to pass through, transmitting a current along the nerve. With chronic pain, parts of this pathway may become hyperactive.
Although many types of ion channels exist, studies have suggested that a sodium channel Nav1.7 may play a central role in chronic pain. If people have mutations in the gene for this channel, they experience extreme, constant pain, or may not experience pain at all.
So Moreno and her team thought they could stop the signals moving to the brain by preventing neurons from producing Nav1.7. Chemists tried to block Nav1.7 with small-molecule drugs and antibodies, but struggled because these therapies also interact with structurally similar sodium channels in the body, causing side effects including numbness and poor coordination. But with CRISPR targeting genes with precision, researchers thought they might be able to hit Nav1.7 directly, without any effects outside the target.
Use CRISPR precision
The team started with a modified version of the Cas9 protein that is normally part of the CRISPR gene processing system. It can cut the DNA sequence encoding Na but notv1.7. The researchers attached a second ‘repressor’ protein to the modified Cas9 that stops the Nav1.7 none is expressed. The researchers packaged this system into a small, inactive virus called an adeno-associated virus that can transmit it into cells.
They gave mice a spinal injection of the gene silence therapy, and then tried to cause chronic pain by injecting chemotherapy drugs or inflammatory drugs into the animals. These mice were more tolerant of painful stimuli. And mice that had already suffered from chronic pain benefited from the therapy, the team showed. For example, mice receiving doses of chemotherapy are very sensitive to pain but lose sensitivity after a single injection of gene therapy. The results were published in Science Translational Medicine on March 101.
In some cases, the pain relief seemed to last up to 44 weeks after the injection. “It’s quite remarkable,” said Sulayman Dib-Hajj, a neuroscientist at Yale University in New Haven, Connecticut.
What is important, says Calvo, seems to be that the treatment destroyed the expression of Nav1.7 without shutting down other sodium channels – the mice lost no feelings except pain, and showed no other side effects.
Despite their excitement, scientists warn that these results are still preliminary, and they do not know whether the pain relief observed in mice will translate to humans. “It gives us hope that gene therapy approaches can work in humans” for the treatment of chronic pain, “says Dib-Hajj,” but more work needs to be done. “
Moreno is now CEO of Navega Therapeutics in San Diego, which plans to continue the treatment with the hope of one day testing it in humans.