At least one in five adults in the US experiences chronic pain, but developing drugs that successfully treat it has been difficult. Fifteen years ago, researchers identified a receptor called NaV1.7 that is central to modulating pain, but numerous attempts to develop drugs that target it have failed, in part because small molecules that act on NaV1.7 tend also to hit closely-related receptors, causing side effects. Now, in a new approach, researchers have used two different gene therapy techniques to tamp down NaV1.7’s expression, successfully eliminating or reducing three different forms of chronic pain in mice without any visible side effects (Sci. Transl. Med. 2021, DOI: 10.1126/scitranslmed.aay9056).
“This is a super exciting paper,” says Rajesh Khanna, a neuroscientist who studies pain at the University of Arizona and who was not involved in the work. “They have taken a well-known target, for which there is difficulty in coming up with a small molecule, and for the first time championed the idea of gene therapy for chronic pain.”
Gene therapies generally make permanent changes to the genome in order to treat rare diseases caused by specific mutations. But the techniques the researchers used here do not permanently disable the gene encoding NaV1.7, explains Ana M. Moreno, CEO of Navega Therapeutics, a company she launched to develop the gene therapy-based pain treatment. Instead, they act to prevent the gene’s expression, so their effects wear off with time.
Moreno first conceived the approach as a graduate student in Prashant Mali’s lab at the University of California, San Diego, investigating ways of using the gene-editing tool CRISPR to activate or repress genes rather than to snip and destroy them. A paper describing an inborn insensitivity to pain in people with mutations disabling the gene for NaV1.7 got her thinking about targeting that receptor as an alternative to drugs, including opioid pain killers, which are addictive and can be deadly. “We don’t want to edit the gene to have a permanent mutation, but if we could regulate or repress it, this could be a really good therapy,” she recalls thinking.
She and her colleagues turned to a variant of CRISPR that uses an inactivated or “dead” version of the enzyme Cas9. As with typical CRISPR, guide RNA sequences target the gene sequence of interest, but while the typical Cas9 enzyme would cut DNA at this site to modify the genome, the dead Cas9 is engineered to simply bind the sequence, hobbling its transcription. To validate their results, they also created a similar tool using an older genome engineering tool that relies on zinc finger proteins. They packaged both therapies into adeno-associated viruses (AAVs), an approach already used to deliver gene therapies, and injected them into the lower spine of mice modeling three different types of pain: inflammatory pain, neuropathic pain induced by chemotherapy, and a more general model of heightened pain sensitivity. The idea was to deliver the therapy to where sensory neurons meet in the spine.
In all types of mice studied, both therapies reduced the expression of NaV1.7 in the region where they were injected. The therapies also reduced pain levels in the mouse models of inflammatory pain and general heightened pain, and appeared to eliminate it entirely for chemotherapy-induced pain. And they seemed to be long-lasting, appearing effective for at least 44 weeks, 3 weeks, and 15 weeks, respectively, without any detectable side effects. The therapies did not affect the animals’ motor function, cognition, or sensory sensitivities such as touch or smell.
It’s not clear how the longevity of these treatments in mice would translate to humans, notes Khanna. But in principle, a long-acting therapy for chronic pain would be welcome, especially considering that it’s similar in timescale to some current chronic pain treatments where people receive steroid injections that last several months, he says. However, he notes that one big unknown is such therapies’ long-term effects, since people with chronic pain might need to receive repeated treatments over decades. “Will it change how people experience pain? Will the frequency of shots needed increase?”
Navega now plans to test the therapies in non-human primates. If these therapies pass the trials, Moreno says, the company hopes to test it in people with a rare disorder called erythromyalgia, in which a NaV1.7 mutation causes oversensitivity to pain. If it succeeds in that context, it could be extended more widely to people with other forms of intractable chronic pain, she says.