An intriguing new proof-of-concept study from a team of University of California San Diego researchers suggests CRISPR gene therapy may be a promising alternative to opioids for chronic pain. The preliminary investigation demonstrated lowered pain sensitivity in mice after temporarily repressing activity of a gene linked to pain states.
The origins of the new study go back to bioengineering researcher Ana Moreno’s time as a Ph.D student working with a unique form of the CRISPR gene editing tool. Moreno was experimenting with a version of CRISPR that doesn’t cut DNA, but instead can block the expression of targeted genes.
Traditional versions of CRISPR gene editing utilize an enzyme called Cas9 as a kind of genetic scissor to cut out targeted genes. This new method uses a dead version of the Cas9 enzyme (dCas9), which doesn’t permanently damage targeted genes but instead smothers and represses its expression.
“It’s not cutting out any genes, so there are no permanent changes to the genome,” explains Moreno. “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.”
During her studies Moreno encountered a research paper discussing a unique genetic mutation found in a few humans who report feeling little to no pain. Called NaV1.7, the gene specifically codes for a protein that is used by pain-transmitting neurons. When NaV1.7 is over-expressed patients can feel heightened sensitivity to pain, but those lacking functional copies of the gene tend to not feel pain strongly.
It’s not cutting out any genes, so there are no permanent changes to the genome
So Moreno and colleagues set out to see if they could deploy their dCas9 method to repress NaV1.7 activity in mice. The preliminary experiments were promising in animal models of chemotherapy pain and inflammatory pain.
The animals tested displayed no adverse effects to general sensitivity but showed higher pain thresholds and decreased signs of discomfort. The therapy was seen to last at least several months, and while it is hypothesized as being a long-lasting therapy it should not be permanent.
“Think of the young athlete or wounded war fighter in which the pain may resolve with wound healing,” says co-senior author Tony Yaksh, a pain expert from UC San Diego. “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.”
The research certainly has a long road ahead before clinical application in humans is a reality. Nevertheless, it is an incredibly fascinating way to approach pain relief, particularly in light of the current problems faced with opioid addiction.
Here is a technique that can temporarily silence a gene known to play a role in pain signaling. And, Moreno suggests NaV1.7 is an exciting target because it doesn’t seem to have any other major role beyond this pain mechanism.
“By targeting this gene, we could alter the pain phenotype,” she says. “What’s also cool is that this gene is only involved in pain. There aren’t any severe side effects observed with this mutation.”
Moreno, Yaksh, and co-senior author Prashant Mali have formed a private company called Navega Therapeutics to further translate dCas9 gene therapies into clinical treatments. The next steps will be to further study efficacy and toxicity for this NaV1.7 therapy in animals before moving to first phase human clinical trials in around two years.
The new study was published in the journal Science Translational Medicine.
Source: UC San Diego
