New gene therapy for chronic pain could replace opioids

With a successful trial in mice, researchers hope that in the future this could be a safer alternative to opioids for pain relief.

Researchers from the University of California San Diego have engineered a gene therapy system to dampen pain. They’ve shown it to be effective in mice, for both short-term and long-term pain.

Now, they are looking to the future — hoping to translate this discovery into a safe alternative to opioids for chronic pain treatment.

Opioid pain relievers are a common chronic pain treatment. They are the standard care for chronic back pain, rare disorders, and pain associated with trauma or chemotherapy. But while opioids mask pain, they can also make people more sensitive to it. Often, people who rely on opioids over time will need higher and higher doses.

“There is a huge opioid epidemic ongoing in the U.S., and we are in need of new treatments for chronic pain that are non-addictive,” Ana Moreno, bioengineering alumni from UC San Diego, said in an email.

When Moreno was a Ph.D. student, she came across a paper about a genetic mutation that causes people to feel no pain. The mutation inactivates a protein (called NaV1.7) in pain transmitting neurons.

People who lack a functional NaV1.7 protein feel no pain. The opposite can also occur: people who have a mutation that leads to an overexpression of the protein feel much more pain.

Moreno realized that by targeting this gene associated with pain, she could change how much pain is registered. And since the gene only involved pain, she believed that targeting it wouldn’t cause any adverse side effects.

Moreno decided to test out gene therapy as a chronic pain treatment in mice, using gene therapy to mask the targeted gene.

CRISPR Cas9 is the most well-known protein used in gene therapy to detect and destroy a targeted gene. The CRISPR Cas9 treatment is effectively permanent. But some pain eventually heals — like someone with significant trauma who takes months to recover, so Moreno didn’t want to remove the pain gene permanently. Instead, she looked at a technique using “dead” Cas9 (dCas9) which can’t cut the DNA. Rather, it sticks to the targeted gene and blocks its expression.

Moreno and her team engineered a CRISPR dCas9 system that targets and suppresses the gene that codes for NaV1.7, then tested it on mice with inflammatory and chemo-induced pain.

They found that the mice that received the chronic pain treatment had a higher pain threshold than those that did not and were also slower to withdraw from pain. After 15 weeks, the treatment was still effective in mice with chemotherapy-induced pain. It was still effective in mice with inflammatory pain after 44 weeks.

The team also tried a second form of chronic pain treatment with a different gene-editing tool, called zinc fingers, and found the same results.

“We were excited that both approaches worked,” co-author Prashant Mali said in a statement.

“The beauty about zinc finger proteins is that they are built on the scaffold of a human protein. The CRISPR system is a foreign protein that comes from bacteria so that it could cause an immune response. That’s why we explored zinc fingers as well, so we have an option that might be more translatable to the clinic.”

Moreno says that the amount of pain relief someone could get from the treatment would depend on how concentrated the dose is. They could dial it back when needed — such as in instances when you want to avoid masking all pain completely. Additionally, they can target specific pain (like lower back pain) by injecting the treatment into related regions of the body.

Moreno and Mali co-founded Navega Therapeutics to translate this into clinical applications, such as a chronic pain treatment for long-lasting pain caused by diabetic polyneuropathy, sciatica, or osteoarthritis.

“Moving ahead, we will be testing multiple doses to ensure it’s safe and doesn’t create issues with masking pain. For specific pain, we can look into where the therapy is injected. For example, in the case of lumbar pain, the therapy can be injected in specific dorsal root ganglia (DRG) that correspond to the lumbar back region,” Moreno said.

Their next step is to test the chronic pain treatment out on non-human primates.

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