By Pat Anson, PNN Editor

A new study by researchers at the University of California San Diego suggests that gene therapy could someday be used to treat a variety of chronic pain conditions without the use of drugs.

In experiments on laboratory mice, researchers found that temporarily repressing a gene involved in sensing pain increases pain tolerance, lowers pain sensitivity and provided months of pain relief without causing numbness. Their findings were published in the journal Science Translational Medicine.

“What we have right now does not work,” said first author Ana Moreno, PhD, CEO of Navega Therapeutics, which is developing gene therapies to treat chronic pain. “There’s a desperate need for a treatment that’s effective, long-lasting and non-addictive.”

Moreno was grad student at UC San Diego studying gene repression when she came across a paper about a genetic mutation that causes humans to feel no pain. The mutation blocks a protein -- called NaV1.7 -- that’s involved in transmitting pain signals in the spinal cord.

That’s when she came up with the idea of suppressing the gene using the CRISPR gene editing tool. Moreno was working with a version of CRISPR that uses what’s called “dead” Cas9, which lacks the ability to permanently cut DNA. Instead, it sticks to a gene and temporarily blocks its expression.

“By targeting this gene, we could alter the pain phenotype,” Moreno explained. “It’s not cutting out any genes, so there are no permanent changes to the genome. You wouldn’t want to permanently lose the ability to feel pain.

“One of the biggest concerns with CRISPR gene editing is off-target effects. Once you cut DNA, that’s it. You can’t go back. With dead Cas9, we’re not doing something irreversible.”

Moreno and UC San Diego bioengineering professor Prashant Mali, PhD, co-founded Navega Therapeutics to work on developing gene therapy as a treatment for pain.  They teamed up with Tony Yaksh, PhD, a professor of anesthesiology and pharmacology at UC San Diego School of Medicine, and developed a CRISPR/dead Cas9 system to target and repress the gene that codes for NaV1.7.

When they administered spinal injections of the system into laboratory mice with inflammatory and chemotherapy-induced pain, the mice displayed higher pain thresholds than mice that did not receive the gene therapy. The treated mice were slower to withdraw a paw from painful stimuli (heat, cold or pressure) and spent less time licking or shaking their paws after being hurt.

The treatment was still effective after 44 weeks in the mice with inflammatory pain and 15 weeks in those with chemotherapy pain. The treated mice did not lose sensitivity or display any changes in normal motor function.

To validate their results, the researchers performed the same tests using another gene editing tool called zinc finger proteins. It’s an older technique than CRISPR, but works the same way. Spinal injections of the zinc fingers into mice produced the same results as the CRISPR-dead Cas9 system.

“We were excited that both approaches worked,” Mali said. “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 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.”

The researchers say this solution could work for a variety of chronic pain conditions, including diabetic neuropathy, sciatica, and chemotherapy pain. They believe their gene therapy platform could also be used to treat short-term acute pain.

“Think of the young athlete or wounded war fighter in which the pain may resolve with wound healing,” Mali explained. “We would not want to permanently remove the ability to sense pain in these people, especially if they have a long-life expectancy. This CRISPR/dead Cas9 approach offers this population an alternative therapeutic intervention—that’s a major step in the field of pain management.”  

Researchers at UC San Diego and Navega are planning further studies of pain-relieving gene therapy on non-human primates. Their goal is to begin human clinical trials in a couple years. Their work is funded by UC San Diego Institutional Funds and the National Institutes of Health.