Gene therapy alleviates chronic pain by reducing sodium levels.

A recent study in the Proceedings of the National Academy of Sciences (PNAS) unveils a groundbreaking gene therapy developed by researchers at NYU College of Dentistry’s Pain Research Center. The therapy targets chronic pain by indirectly modulating a specific sodium ion channel, NaV1.7, a critical player in pain signal generation and transmission. The research, led by Rajesh Khanna, Director of the NYU Pain Research Center, demonstrates the effectiveness of the innovative therapy in cell and animal testing, made possible by pinpointing the exact region where a regulatory protein binds to NaV1.7, influencing its activity.

Chronic pain, a pervasive public health concern affecting approximately one-third of the U.S. population, has spurred a quest for more potent and safer alternatives to opioids. Sodium ion channels, especially NaV1.7, have gained attention due to their role in nerve cell communication, particularly in rare genetic pain disorders where mutations either intensify or eliminate pain.

While traditional approaches have sought to directly block NaV1.7, Khanna’s strategy involves the indirect regulation of this channel using a protein known as CRMP2. CRMP2 interacts with NaV1.7, modulating its activity and, consequently, the amount of sodium entering the channel, ultimately alleviating pain.

Khanna’s team previously developed a successful small molecule that indirectly regulates NaV1.7 through CRMP2 targeting, showing promise in controlling pain in cells and animal models. Despite this success, a key question remained: why does CRMP2 selectively communicate with NaV1.7 and not the other eight sodium ion channels in the same family?

The PNAS study sheds light on this specificity, identifying a distinct region within NaV1.7 where CRMP2 binds to regulate its activity. This specificity was confirmed as CRMP2 did not readily bind to other sodium ion channels.

Excitement grew within the research team as the removal of this specific region from the NaV1.7 channel led to the loss of CRMP2 regulation. To disrupt the communication between CRMP2 and NaV1.7, the researchers created a peptide from the channel, corresponding to the binding region of CRMP2. This peptide was then inserted into an adeno-associated virus for delivery to neurons, successfully inhibiting NaV1.7.

The engineered virus, carrying a small piece of genetic material from a common protein, was administered to mice experiencing various forms of pain, including sensitivity to touch, heat, cold, and chemotherapy-induced peripheral neuropathy. Remarkably, within a week to 10 days, the researchers observed a reversal of pain in the animals.

Khanna expressed enthusiasm about this breakthrough in gene therapy for pain treatment, emphasizing its potential as a transformative moment in the field. The researchers validated their findings across multiple species, including rodents, primates, and human cells, signaling a promising path toward translating this approach into a treatment for humans.

The study, supported by the National Institute of Neurological Disorders and Stroke (NS098772, NS120663, and NS119263) and the National Institute on Drug Abuse (DA042852), involves researchers from various institutions, including NYU Dentistry, the University of Arizona, Virginia Commonwealth University, and St. Louis University. Khanna and several co-authors have founded biotech companies (Regulonix LLC and ElutheriaTx Inc.) to develop non-opioid drugs for chronic pain and hold patents on the described technology.

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