Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1
Tetrahydrobiopterin (BH4) expression is normally strictly controlled; however, its intracellular levels increase considerably following nerve damage. GTP cyclohydrolase I (GCH1) plays a crucial role in regulating BH4 concentration, with an upregulation observed in the dorsal root ganglion in cases o...
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| Format: | Article |
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Elsevier
2025-03-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747924001983 |
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| author | Heesue Chang Kyoung Jin Lee Minkyung Park Ha-Na Woo Ji Hyun Kim Im Kyeung Kang Hyochan Park Chan Hee Chon Heuiran Lee Hyun Ho Jung |
| author_facet | Heesue Chang Kyoung Jin Lee Minkyung Park Ha-Na Woo Ji Hyun Kim Im Kyeung Kang Hyochan Park Chan Hee Chon Heuiran Lee Hyun Ho Jung |
| author_sort | Heesue Chang |
| collection | DOAJ |
| description | Tetrahydrobiopterin (BH4) expression is normally strictly controlled; however, its intracellular levels increase considerably following nerve damage. GTP cyclohydrolase I (GCH1) plays a crucial role in regulating BH4 concentration, with an upregulation observed in the dorsal root ganglion in cases of neuropathic pain. In this study, we aimed to develop and evaluate the clinical potential of an RNA interference-based adeno-associated virus (AAV) targeting GCH1 across various species to decrease BH4 levels and, consequently, alleviate neuropathic pain symptoms. We identified universal small-interfering RNA sequences effective across species and developed an AAV-u-shRNA that successfully suppressed GCH1 expression with minimal off-target effects. Male Sprague Dawley rats were divided into four groups: normal, spared nerve injury, AAV-shCON, and AAV-u-shGCH1. The rats were sacrificed on post-injection day 28 to collect blood for BH4 level assessment. The AAV-u-shGCH1 group demonstrated remarkable improvement in the mechanical withdrawal threshold by PID 28, significantly outperforming the normal, spared nerve injury, and AAV-shCON groups. Plasma BH4 levels confirmed that AAV-u-shGCH1 effectively reduced neuropathic pain by inhibiting BH4 synthesis in vivo, introducing a novel, multispecies-compatible therapeutic strategy. Our results suggest that a single application of AAV-u-shGCH1 could offer a viable solution for neuropathic pain relief. |
| format | Article |
| id | doaj-art-8a8a78fc47534766b452819ae3c1caff |
| institution | OA Journals |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-8a8a78fc47534766b452819ae3c1caff2025-08-20T02:18:00ZengElsevierNeurotherapeutics1878-74792025-03-01222e0051110.1016/j.neurot.2024.e00511Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1Heesue Chang0Kyoung Jin Lee1Minkyung Park2Ha-Na Woo3Ji Hyun Kim4Im Kyeung Kang5Hyochan Park6Chan Hee Chon7Heuiran Lee8Hyun Ho Jung9Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of KoreaDivision of Systems Neuroscience, Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), and Research Foundation for Mental Hygiene, Inc. (RFMH), New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USABio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Biochemistry & Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of KoreaDepartment of Microbiology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaInventage Lab, Seongnam, Republic of KoreaInventage Lab, Seongnam, Republic of KoreaBio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Microbiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea; Corresponding authors.Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Neurosurgery, Brain Research institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Corresponding authors.Tetrahydrobiopterin (BH4) expression is normally strictly controlled; however, its intracellular levels increase considerably following nerve damage. GTP cyclohydrolase I (GCH1) plays a crucial role in regulating BH4 concentration, with an upregulation observed in the dorsal root ganglion in cases of neuropathic pain. In this study, we aimed to develop and evaluate the clinical potential of an RNA interference-based adeno-associated virus (AAV) targeting GCH1 across various species to decrease BH4 levels and, consequently, alleviate neuropathic pain symptoms. We identified universal small-interfering RNA sequences effective across species and developed an AAV-u-shRNA that successfully suppressed GCH1 expression with minimal off-target effects. Male Sprague Dawley rats were divided into four groups: normal, spared nerve injury, AAV-shCON, and AAV-u-shGCH1. The rats were sacrificed on post-injection day 28 to collect blood for BH4 level assessment. The AAV-u-shGCH1 group demonstrated remarkable improvement in the mechanical withdrawal threshold by PID 28, significantly outperforming the normal, spared nerve injury, and AAV-shCON groups. Plasma BH4 levels confirmed that AAV-u-shGCH1 effectively reduced neuropathic pain by inhibiting BH4 synthesis in vivo, introducing a novel, multispecies-compatible therapeutic strategy. Our results suggest that a single application of AAV-u-shGCH1 could offer a viable solution for neuropathic pain relief.http://www.sciencedirect.com/science/article/pii/S1878747924001983Neuropathic painAdeno-associated virusTetrahydrobiopterinGTP cyclohydrolase IRNA interferenceMultispecies-compatibility |
| spellingShingle | Heesue Chang Kyoung Jin Lee Minkyung Park Ha-Na Woo Ji Hyun Kim Im Kyeung Kang Hyochan Park Chan Hee Chon Heuiran Lee Hyun Ho Jung Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1 Neurotherapeutics Neuropathic pain Adeno-associated virus Tetrahydrobiopterin GTP cyclohydrolase I RNA interference Multispecies-compatibility |
| title | Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1 |
| title_full | Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1 |
| title_fullStr | Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1 |
| title_full_unstemmed | Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1 |
| title_short | Cross-species RNAi therapy via AAV delivery alleviates neuropathic pain by targeting GCH1 |
| title_sort | cross species rnai therapy via aav delivery alleviates neuropathic pain by targeting gch1 |
| topic | Neuropathic pain Adeno-associated virus Tetrahydrobiopterin GTP cyclohydrolase I RNA interference Multispecies-compatibility |
| url | http://www.sciencedirect.com/science/article/pii/S1878747924001983 |
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