Gene Therapy for Back Pain and Other Chronic Pain

Researchers at UC San Diego have developed a gene therapy strategy for chronic pain. It may provide better results than alternatives such as anti-inflammatories, opioids, physical therapy, spinal fusion surgery, or stem cell therapy.

"What we have right now does not work," said UC San Diego bioengineer Ana Moreno, first author of the study. "There's a desperate need for a treatment that's effective, long-lasting and non-addictive.”

The new therapy is described in a study published in Science Translational Medicine. It works by temporarily repressing a gene involved in sensing pain. The study reports that the researchers used the new therapy to increase pain tolerance in laboratory mice, lower their sensitivity to pain, and provide pain relief without causing numbness, both short- and long-term (many weeks).

The new gene therapy could be used to provide treatment options for a broad range of chronic pain conditions. It could treat back pain due to painful discs, damaged discs, disc herniation, disc degeneration, or degenerative disc disease (DDD). It could provide treatment options for neuropathic pain disorders, diabetic polyneuropathy, erythromelalgia, sciatica, and osteoarthritis. And it could also provide relief for patients undergoing chemotherapy.

The researchers used a version of the cut-and-paste gene editing technology CRISPR. The version of CRISPR used by the researchers relies on what's called "dead" Cas9, which lacks the ability to cut DNA. Instead, it sticks to a gene target and blocks its expression.

The researchers used this approach to deactivate a gene in the spinal cord. By deactivating the gene, they repressed production of NaV1.7, which is a protein that is over-expressed in pain-transmitting neurons. The approach doesn't appear to affect other aspects of the spine, such as disc height, the nucleus pulposus, or genes in spinal disc cells.

Moreover, the new gene therapy is “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," said Moreno. "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."

"In some common diseases, the issue is that a gene is being misexpressed. You don't want to completely shut it down," added UC San Diego bioengineering professor Prashant Mali. "But if you could turn down the dose of that gene, you could bring it to a level where it is not pathogenic. That is what we are doing here. We don't completely take away the pain phenotype, we dampen it."

This approach “is superclever,” note experts not directly involved in the study, as reported in a commentary published in Science News. While cost could prevent a genetic strategy from becoming a treatment for a condition as common as chronic pain, this is a step in the right direction.

The researchers also performed the same tests using an older gene editing tool called "zinc finger proteins," with similar results. Zinc finger proteins are derived from human proteins, and don’t cause immune responses. Therefore, pain treatments based on zinc finger proteins could be a better approach in practical medicine.

Moreno and Mali co-founded the spinoff company Navega Therapeutics to work on preparing this gene therapy approach for clinical trials. They developed the approach at UC San Diego.