PainRelief.com Interview with:
Rajesh Khanna, PhD
Director, NYU Pain Research Center
Professor, Department of Molecular Pathobiology
Professor, Department of Neuroscience and Physiology
Investigator, Neuroscience Institute
New York University
PainRelief.com: What is the background for this study?
Response: Chronic pain affects an estimated 20-30% of the global population, significantly impacting quality of life and mental health. It poses substantial socioeconomic burdens, with costs relating to healthcare and lost productivity. Despite its prevalence, chronic pain remains underdiagnosed and undertreated worldwide, highlighting a crucial need for enhanced awareness, research, and therapeutic strategies.
Among the many targets being pursued for the development of drugs against chronic pain conditions are key proteins in neurons that are involved in the signaling of pain. A key family of these targets is the voltage-gated sodium channel family. Among them, the Nav1.7 sodium channel plays a critical role in the development and maintenance of chronic pain. It is an integral part of the peripheral nervous system and is highly expressed in nociceptive (pain-sensing) neurons, including the dorsal root ganglia and sympathetic ganglion neurons.
Nav1.7 channels act as a threshold channel, amplifying small sub-threshold depolarizations and generating action potentials, which are the electrical signals responsible for transmitting sensory information, including pain, to the brain. In essence, they work as a key amplifier of signals from peripheral pain-sensing neurons to central pain pathways.
Certain genetic mutations that cause either a gain or loss of Nav1.7 function can lead to conditions associated with altered pain perception. Gain-of-function mutations, which increase the activity of the channel, can lead to pain syndromes like Inherited Erythromelalgia (IE) and Paroxysmal Extreme Pain Disorder (PEPD). In contrast, loss-of-function mutations, which decrease or eliminate the activity of Nav1.7, result in Congenital Insensitivity to Pain (CIP), a condition where individuals are unable to feel pain.
Given this integral role, Nav1.7 has become a focus of interest as a target for new analgesic drugs. The development of Nav1.7 inhibitors could offer a new avenue for more effective and targeted treatment strategies for chronic pain conditions. It’s a promising area of research, though there are still challenges to be met, such as achieving sufficient specificity for the Nav1.7 channel to avoid side effects associated with other sodium channels.
In the NYU Pain Research Center in the College of Dentistry at New York University (https://dental.nyu.edu/research/pain-research-center.html), the Khanna lab is pursuing alternative ways to target Nav1.7 for pain relief.
PainRelief.com: What are the main findings?
Response: In 2013, the Khanna lab identified a protein that could control the activity of Nav1.7. This was the collapsin response mediator protein 2 (CRMP2), a multifunctional protein involved in neuronal differentiation and axonal guidance. It is crucial for the trafficking and modulation of several channels and receptors within neurons, including voltage-gated calcium and sodium channels. They went to identify alterations in CRMP2 as being associated with increased pain sensitivity in experimental models. Further work showed that CRMP2 interacts directly with Nav1.7, modulates its function, and that this interaction may have implications for pain signal transmission.
A question that remained unanswered is how CRMP2 controlled only Nav1.7 and not the other 8 members of the Nav family. Now, in this paper (https://pubmed.ncbi.nlm.nih.gov/37498871/), the Khanna lab provides answers to the specificity of this coupling. We show that a unique intracellular region in Nav1.7, susceptible to regulation by CRMP2, offers a novel target to alleviate chronic pain. The lab showed that targeting this sequence effectively reverses mechanical allodynia, a pain response to a typically non-painful stimulus, in preclinical models of nerve injury and chemotherapy-induced peripheral neuropathy. Delivering a plasmid coding for this sequence via a viral capsid decreased Nav1.7 current density and neuropathic pain. This approach’s translational value is demonstrated by its efficacy in reducing NaV1.7 function in macaque dorsal root ganglion (DRG) neurons, which show complete sequence homology with human NaV1.7.
PainRelief.com: What should readers take away from your report?
Response: With a fresh approach to tackling pain, we are harnessing the power of gene therapy. Outclassing traditional drug regimens that demand daily doses, this method offers a game-changing solution – treating chronic conditions with a one-time treatment. We have built our strategy upon a unique domain regulating Nav1.7, the cornerstone of our genetic therapy approach. Our technique, using viral delivery of the Nav1.7 peptide, not only reverses chronic neuropathic pain, whether caused by injury or chemotherapy, but also halts its onset if administered pre-injury. The unique sequence targeting suggests it could be a disease modifier and a treatment for existing chronic pain. Throughout our month-long study following viral injection, we saw zero signs of toxicity, indicating the treatment’s safety. Our additional checks on motor behavior and anxiety hint at a robust safety profile for sustained inhibition of NaV1.7’s peptide domain, solidifying its potential as a potentially groundbreaking treatment.
PainRelief.com: What recommendations do you have for future research as a result of this study?
Response: While our results offer a beacon of hope, it is important to temper expectations as we are still several strides away from clinical application. As we venture further into the realm of viral delivery and gene editing technologies, we must tread carefully, ensuring these approaches are refined and safe for human use. The peptide we have identified holds great potential for chronic pain gene therapy, but we must proceed with caution and meticulous scrutiny every step of the way.
Gomez K, Stratton HJ, Duran P, Loya S, Tang C, Calderon-Rivera A, François-Moutal L, Khanna M, Madura CL, Luo S, McKiver B, Choi E, Ran D, Boinon L, Perez-Miller S, Damaj MI, Moutal A, Khanna R. Identification and targeting of a unique NaV1.7 domain driving chronic pain. Proc Natl Acad Sci U S A. 2023 Aug 8;120(32):e2217800120. doi: 10.1073/pnas.2217800120. Epub 2023 Jul 27. PMID: 37498871.
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Last Updated on August 2, 2023 by PainRelief.com