A team of researchers—including Yale School of Medicine’s Sulayman D. Dib-Hajj, PhD, senior research scientist in neurology, Stephen G. Waxman, MD, PhD, professor of neurology, and Lakshmi Bangalore, PhD, lecturer in neurology—has been awarded funding through the NIH HEAL Initiative: Team Research for Initial Translational Efforts in Non-addictive Analgesic Therapeutics Development. The team also includes Joshua Rosenthal, PhD, senior scientist, The Marine Biological Laboratory, who is the coordinating lead investigator, Gregory Dussor, PhD, professor of neuroscience, and Theodore J Price, professor of neuroscience, The University of Texas at Dallas, and Eli Eisenberg, professor of physics, Tel Aviv University.
The Helping to End Addiction Long-termSM Initiative, or NIH HEAL Initiative, is an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Almost every NIH Institute and Center is accelerating research to address this public health emergency from all angles, including the development of non-opioid treatments for chronic pain. The $11.9 million grant, titled “Site-directed RNA editing of Nav1.7 as a novel analgesic,” will build upon discoveries at Yale and VA Connecticut, which have indicted sodium channel Nav1.7 as a master controller of pain. Along with studies in animal models, the Yale team has shown that genetic mutations that ramp up activity of Nav1.7 cause extreme pain disorders whereas those that impair Nav1.7 activity lead to marked insensitivity to pain. Over a period of five years this grant will support research to develop site-directed RNA editing of Nav1.7 as a novel analgesic.
This research effort will use RNA editing, which consists of intercepting and modifying the molecular transcript of the DNA code on its way to the cell’s protein-making machinery where proteins such as Nav1.7 are built. Over the next five years, the multidisciplinary team with expertise in molecular neuroscience, neurobiology of pain and its co-morbidities, pharmacology, physiology, and bioinformatics, will work to advance RNA editing technology to modify Nav1.7 in a manner that calms overactive pain-signaling nerves. The study aims to generate preclinical validation as a step toward human clinical trials.
There are multiple advantages to this gene therapy approach notes Dib-Hajj, the Yale principal investigator for the project. “First, because it targets a subset of neurons, namely pain-signaling neurons, it is highly selective and thus is expected to avoid off-target side effects including the potential for addiction. Second, unlike DNA editing which permanently alters the genome and could potentially have unintended effects, RNA editing is transient and allows for temporary fixes for just the amount of time needed to alleviate pain.”
“The research data generated from this work will be shared as part of the HEAL Data Ecosystem that encompasses all HEAL projects,” says Bangalore who will lead the data management core for the project. “Working within this large Ecosystem, our results will have increased impact.”
“We are capitalizing on two decades of research at Yale and VA Connecticut validating Nav1.7 channel as a target for novel, effective, safer, and non-addictive treatment for pain,” says Waxman. “Our collaboration with four other teams, and our partnership with the NIH will increase the likelihood that we can build on our work on Nav1.7 to mute chronic pain.”