Gene Therapy Treats Chronic Pain by Dialing Down Sodium

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Researchers at NYU College of Dentistry’s Pain Research Center have made a significant breakthrough in developing a gene therapy for treating chronic pain, according to a study published in the Proceedings of the National Academy of Sciences (PNAS). The therapy, which has been tested in cells and animals, indirectly regulates a specific sodium ion channel known as NaV1.7, by targeting a regulatory protein that binds to the channel and controls its activity.

Chronic pain affects approximately one-third of the U.S. population and finding effective and safer alternatives to opioids has become a priority for scientists. Sodium ion channels play a crucial role in pain generation and transmission as they are vital for nerve cell communication. NaV1.7 has been identified as an ideal target for pain treatment due to its importance in individuals with rare genetic pain disorders. Mutations in the gene encoding NaV1.7 can either cause intense chronic pain or result in a complete inability to feel pain.

Previous attempts to develop pain treatments to selectively block NaV1.7 have been largely unsuccessful. However, Rajesh Khanna, director of the NYU Pain Research Center, took a different approach by focusing on indirect regulation of NaV1.7 using a protein called CRMP2. By inhibiting the interaction between CRMP2 and NaV1.7, Khanna’s team was able to control the amount of sodium entering the channel, which reduced pain.

Now, the researchers have identified the precise region within NaV1.7 where CRMP2 binds to regulate its activity. They discovered that this region is specific to NaV1.7 and does not readily bind to other sodium ion channels. Excitingly, by removing this particular region of the NaV1.7 channel, the regulation by CRMP2 was lost.

To limit the communication between CRMP2 and NaV1.7, the researchers created a peptide from the channel that corresponds to the binding region of CRMP2. They inserted this peptide into an adeno-associated virus, which efficiently delivered it to neurons to inhibit NaV1.7. Gene therapy using viruses to transport genetic material to cells has shown success in various medical fields, and in this case, it was administered to mice experiencing pain. After a week to 10 days, the researchers observed a reversal of pain symptoms.

The findings were replicated in multiple species, including rodents, primates, and humans. However, further studies are required to validate the approach in humans. The long-term goal is to develop a gene therapy that can be used to treat painful conditions, including chemotherapy-induced neuropathy.

The study was supported by the National Institute of Neurological Disorders and Stroke and the National Institute on Drug Abuse. Rajesh Khanna and several co-authors are co-founders of biotech companies focused on developing non-opioid drugs for chronic pain. They also hold patents on the technology used in the study.

Founded in 1865, NYU College of Dentistry is the third oldest and the largest dental school in the US, educating nearly 10 percent of the nation’s dentists. The college has a diverse student body and a significant global reach.

In summary, the researchers at NYU College of Dentistry have developed a gene therapy that indirectly regulates a specific sodium ion channel to treat chronic pain. This innovative therapy has shown promising results in cells and animals, and further studies are underway to advance its use in humans. The findings offer hope for developing more effective and safer pain medications, addressing a significant public health issue.

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