Chronic Pain Treatment using Gene Therapy; Study Finds

According to a new study published in the Proceedings of the National Academy of Sciences (PNAS), researchers from NYU College of Dentistry’s Pain Research Center have discovered a gene therapy that cures chronic pain by indirectly controlling a specific sodium ion channel.

The finding of the specific location where a regulatory protein binds to the NaV1.7 sodium ion channel to control its activity enables the novel therapy, which has been tested in cells and animals.

“Our study represents a major step forward in understanding the underlying biology of the NaV1.7 sodium ion channel, which can be harnessed to provide relief from chronic pain,” said Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology at NYU Dentistry.

Chronic pain is a major public health concern that affects nearly one-third of the American population. Scientists are keen to create pain treatments that are both more effective and safer than opioids.

Sodium ion channels are important in the creation and transmission of pain because they allow nerve cells, or neurons, to communicate with one another. Following the revelation of its importance in patients with uncommon, genetic pain illnesses, one specific sodium ion channel termed NaV1.7 emerged as a possible target for pain treatment. In some families, a mutation in the NaV1.7 gene allows high amounts of sodium to enter cells, resulting in severe chronic pain. In some families, mutations that block NaV1.7 cause total pain relief.

Scientists have been attempting to produce pain medications that selectively block NaV1.7 for years, with little success. Khanna has chosen a different approach: rather than suppressing NaV1.7, he hopes to regulate it indirectly via a protein called CRMP2.

“CRMP2 ‘talks’ to the sodium ion channel and modulates its activity, allowing more or less sodium into the channel. If you block the conversation between Nav1.7 and CRMP2 by inhibiting the interaction between the two, we can dial down how much sodium comes in. This quiets down the neuron and pain is mitigated,” said Khanna, the PNAS study’s senior author.

Khanna’s lab earlier created a tiny chemical that modulates Nav1.7 expression indirectly by targeting CRMP2. The molecule has been shown to be effective in regulating pain in cells and animal models, and research into its usage in people is ongoing. Despite the compound’s performance, one important question remained: why does CRMP2 exclusively communicate with the NaV1.7 sodium ion channel and not the other eight sodium ion channels in the same family?

The researchers identified a specific location within NaV1.7 where the CRMP2 protein interacts to the sodium ion channel to regulate its activity in their investigation. CRMP2 did not readily attach to other sodium ion channels, indicating that this area is unique to NaV1.7.

“This got us really excited, because if we took out that particular piece of the NaV1.7 channel, the regulation by CRMP2 was lost,” said Khanna.

The researchers generated a peptide from the channel that matches to the region where CRMP2 binds to NaV1.7 in order to inhibit communication between CRMP2 and NaV1.7. They combined the peptide with an adeno-associated virus to deliver it to neurons and inhibit NaV1.7. Using viruses to deliver genetic material to cells is a cutting-edge strategy in gene therapy that has resulted in therapeutic therapies for blood problems, eye ailments, and other rare conditions.

The modified virus was administered to mice suffering from pain, such as sensitivity to touch, heat, or cold, as well as chemotherapy-induced peripheral neuropathy. The animals’ suffering was reversed within a week to ten days, according to the researchers.

“We found a way to take an engineered virus—containing a small piece of genetic material from a protein that all of us have—and infect neurons to effectively treat pain,” said Khanna. We are at the precipice of a major moment in gene therapy, and this new application in chronic pain is only the latest example.

The researchers duplicated their findings by suppressing NaV1.7 function in rodents as well as cells from primates and humans. While further research is needed, this is an encouraging sign that their strategy will convert into a human treatment.

“There is a significant need for new pain treatments, including for cancer patients with chemotherapy-induced neuropathy. Our long-term goal is to develop a gene therapy that patients could receive to better treat these painful conditions and improve their quality of life,” said Khanna.

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