New Gene Therapy to Treat Chronic Pain

Researchers have developed a gene therapy that treats chronic pain by indirectly regulating a specific sodium ion channel, according to a new study published.

The innovative therapy is made possible by the discovery of the precise region where a regulatory protein binds to the NaV1.7 sodium ion channel to control its activity.

Sodium ion channels play a key role in the generation and transmission of pain, as they are critical for nerve cells, or neurons, communicating with each other. One particular sodium ion channel called NaV1.7 emerged as a promising target for treating pain following the discovery of its importance in people with rare, genetic pain disorders. In some families, a mutation in the gene that encodes for NaV1.7 allows large amounts of sodium to enter cells, causing intense chronic pain. In other families, mutations that block NaV1.7 result in a complete lack of pain.

Scientists have been trying for years to develop pain treatments to selectively block NaV1.7 — with little success. Khanna has taken a different approach: rather than blocking NaV1.7, his goal is to indirectly regulate it using 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.

Khanna’s lab previously developed a small molecule that indirectly regulates Nav1.7 expression through targeting CRMP2. But despite the compound’s success, a key question remained: why does CRMP2 only communicate with the NaV1.7 sodium ion channel, and not the eight other sodium ion channels in the same family?

The researchers pinpointed a specific region within NaV1.7 where the CRMP2 protein binds to the sodium ion channel in order to regulate its activity. They learned that this region is specific to NaV1.7, as CRMP2 did not readily bind to other sodium ion channels.

To limit the communication between CRMP2 and NaV1.7, the researchers created a peptide from the channel that corresponds to the region where CRMP2 binds to NaV1.7. They inserted the peptide into an adeno-associated virus in order to deliver it to neurons and inhibit NaV1.7.

The engineered virus was given to mice experiencing pain, including sensitivity to touch, heat, or cold, as well as peripheral neuropathy that results from chemotherapy. After a week to 10 days, the researchers’ assessed the animals and found that their pain was reversed.

“We found a way to take an engineered virus and infect neurons to effectively treat pain,” said Khanna. 

The researchers replicated their findings inhibiting NaV1.7 function across multiple species, including rodents and the cells of primates and humans. While more studies are needed, this is a promising sign that their approach will translate into a treatment for humans.

Sources:

Kimberly Gomez, Harrison J. Stratton, Paz Duran, Santiago Loya, Cheng Tang, Aida Calderon-Rivera, Liberty François-Moutal, May Khanna, Cynthia L. Madura, Shizhen Luo, Bryan McKiver, Edward Choi, Dongzhi Ran, Lisa Boinon, Samantha Perez-Miller, M. Imad Damaj, Aubin Moutal, Rajesh Khanna. Identification and targeting of a unique Na V 1.7 domain driving chronic pain. Proceedings of the National Academy of Sciences, 2023; 120 (32) DOI: 10.1073/pnas.2217800120

New York University. “Gene therapy treats chronic pain by dialing down sodium.” ScienceDaily. ScienceDaily, 27 July 2023. <www.sciencedaily.com/releases/2023/07/230727212040.htm>.

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