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Brain : a Journal of Neurology Sep 2023Chronic pain affects millions of people worldwide and new treatments are needed urgently. One way to identify novel analgesic strategies is to understand the biological...
Chronic pain affects millions of people worldwide and new treatments are needed urgently. One way to identify novel analgesic strategies is to understand the biological dysfunctions that lead to human inherited pain insensitivity disorders. Here we report how the recently discovered brain and dorsal root ganglia-expressed FAAH-OUT long non-coding RNA (lncRNA) gene, which was found from studying a pain-insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses in patient-derived cells we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed. Given that FAAH is a potential target for the treatment of pain, anxiety, depression and other neurological disorders, this new understanding of the regulatory role of the FAAH-OUT gene provides a platform for the development of future gene and small molecule therapies.
Topics: Humans; RNA, Long Noncoding; Pain; Analgesics; Ganglia, Spinal
PubMed: 37222214
DOI: 10.1093/brain/awad098 -
Proceedings of the National Academy of... Aug 2023Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small...
Small molecules directly targeting the voltage-gated sodium channel (VGSC) Na1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the Na1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked Na1.7 function and was antinociceptive in rodent models of neuropathic pain. Here, we discovered a CRMP2 regulatory sequence (CRS) unique to Na1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the Na1.7 CRS over other Na isoforms. Substitution of the Na1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased Na1.7 currents. A cell-penetrant decoy peptide corresponding to the Na1.7-CRS reduced Na1.7 currents and trafficking, decreased presynaptic Na1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the Na1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a Na1.7 -targeted gene therapy, we packaged a plasmid encoding the Na1.7-CRS in an AAV virus. Treatment with this virus reduced Na1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy. These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.
Topics: Animals; Hyperalgesia; Chronic Pain; Macaca mulatta; Neuralgia; NAV1.7 Voltage-Gated Sodium Channel; Ganglia, Spinal; NAV1.8 Voltage-Gated Sodium Channel
PubMed: 37498871
DOI: 10.1073/pnas.2217800120