Targeted gene delivery to nociceptors

The National Institute of Dental and Craniofacial Research awarded Brigham & Women's Hospital Inc. $160,704 on September 12, 2026, under the Oral Diseases and Disorders Research program (CFDA 93.121) to develop a viral gene therapy strategy for treating chronic craniofacial and dental pain caused by trigeminal nociceptor activation.

The funded research will identify gene enhancers uniquely active in trigeminal ganglion nociceptors and functionally screen adeno-associated viruses (AAVs) designed for trigeminal nociceptor-specific gene expression. The work employs single-cell transcriptomics and epigenomics to isolate cis-regulatory elements that enable selective silencing of trigeminal pain-sensing neurons while sparing other peripheral and central nervous system cell types. The project addresses the limitation of current viral vectors, which lack the ability to distinguish between sensory neuron subtypes, by using these regulatory elements to drive viral gene expression specifically in trigeminal nociceptors. This approach permits local administration to affected nerves or ganglia in a single dose, avoiding systemic distribution and associated off-target effects of current pain treatments.

Brigham & Women's Hospital, a subsidiary of Partners Healthcare System Incorporated based in Boston, Massachusetts, is the recipient. Performance occurs in Boston, MA. The period of performance extends from the award date through May 31, 2029. This is a Project Grant, an assistance type under NIDCR's extramural research program supporting basic, translational, and clinical research in dental, oral, and craniofacial health and disease.

Abstract

Chronic pain presents as a significant source of disability for large numbers of people in the U.S. Of these patients, many suffer from chronic craniofacial and dental pain which is caused by the continuous activation of trigeminal pain sensing neurons (nociceptors). Conditions like trigeminal neuralgia, for instance, are associated with significant morbidity and higher suicide rates. In addition, the current treatments for such persistent pain are limited and often come with debilitating side effects due to their off-target effects. This proposal aims to address this issue by developing an innovative gene therapy strategy designed to selectively silence trigeminal nociceptors while sparing other cell types in the peripheral and central nervous systems. Viral gene therapy is particularly promising for treating intractable craniofacial and dental pain, as IT can be administered locally in a single dose to the affected nerve or ganglia, avoiding systemic distribution. Additionally, viral gene therapies are well-positioned for clinical translation, with several already approved by the FDA and many others in trials for neurological disorders. However, current viral vectors lack the ability to distinguish between sensory neuron subtypes, limiting their effectiveness for treating pain. To overcome this, we propose using recent breakthroughs in single-cell transcriptomics and epigenomics to identify CIS regulatory elements, such as gene enhancers, that can drive viral gene expression specifically in trigeminal nociceptors. This proposal outlines two specific aims: 1) identifying gene enhancers uniquely active in trigeminal ganglion nociceptors, and 2) functionally screening aavs (adeno-associated viruses) designed for trigeminal nociceptor specificity. In the first aim, we will perform single-cell epigenomic profiling of trigeminal ganglia from mice and humans to prioritize putative enhancers that regulate nociceptor-specific gene expression across species. In the second aim, we will create a library of viruses where each candidate enhancer drives expression of a unique molecular barcode, followed by in vivo screening using single-nucleus RNA sequencing to identify barcodes expressed primarily in trigeminal nociceptors. Successful completion of this project will produce nociceptor-specific viral tools for pain research. We also anticipate that these enhancers, which would be conserved across species, will enable similar cell-type specificity in humans. Ultimately, these vectors can be engineered to express inhibitory ION channels (e.g., chemogenetic or optogenetic), offering researchers and patients a non-opioid, on-demand solution for craniofacial and dental pain relief.