Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve
Neuropathic pain, a heterogeneous condition, affects 7%–10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-06-01
|
| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122001196 |
| _version_ | 1811249048736235520 |
|---|---|
| author | Hidetoshi Kaburagi Tetsuya Nagata Mitsuhiro Enomoto Takashi Hirai Masaki Ohyagi Kensuke Ihara Kie Yoshida-Tanaka Satoe Ebihara Ken Asada Hiroyuki Yokoyama Atsushi Okawa Takanori Yokota |
| author_facet | Hidetoshi Kaburagi Tetsuya Nagata Mitsuhiro Enomoto Takashi Hirai Masaki Ohyagi Kensuke Ihara Kie Yoshida-Tanaka Satoe Ebihara Ken Asada Hiroyuki Yokoyama Atsushi Okawa Takanori Yokota |
| author_sort | Hidetoshi Kaburagi |
| collection | DOAJ |
| description | Neuropathic pain, a heterogeneous condition, affects 7%–10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease. |
| first_indexed | 2024-04-12T15:39:41Z |
| format | Article |
| id | doaj.art-22296da924d746c2af59bc6a87710a40 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-12T15:39:41Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-22296da924d746c2af59bc6a87710a402022-12-22T03:26:51ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-06-0128910919Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerveHidetoshi Kaburagi0Tetsuya Nagata1Mitsuhiro Enomoto2Takashi Hirai3Masaki Ohyagi4Kensuke Ihara5Kie Yoshida-Tanaka6Satoe Ebihara7Ken Asada8Hiroyuki Yokoyama9Atsushi Okawa10Takanori Yokota11Department of Orthopedic and Spinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan; Corresponding author Dr. Tetsuya Nagata, Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.Department of Orthopedic and Spinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Orthopedic and Spinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Orthopedic and Spinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Orthopedic and Spinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanDepartment of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan; Corresponding author Dr. Takanori Yokota, Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, Japan.Neuropathic pain, a heterogeneous condition, affects 7%–10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease.http://www.sciencedirect.com/science/article/pii/S2162253122001196MT: Oligonucleotides: Therapies and Applicationsantisense oligonucleotideDNA/RNA heteroduplexdorsal root ganglionneuropathic painsciatic nerve |
| spellingShingle | Hidetoshi Kaburagi Tetsuya Nagata Mitsuhiro Enomoto Takashi Hirai Masaki Ohyagi Kensuke Ihara Kie Yoshida-Tanaka Satoe Ebihara Ken Asada Hiroyuki Yokoyama Atsushi Okawa Takanori Yokota Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications antisense oligonucleotide DNA/RNA heteroduplex dorsal root ganglion neuropathic pain sciatic nerve |
| title | Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve |
| title_full | Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve |
| title_fullStr | Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve |
| title_full_unstemmed | Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve |
| title_short | Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve |
| title_sort | systemic dna rna heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve |
| topic | MT: Oligonucleotides: Therapies and Applications antisense oligonucleotide DNA/RNA heteroduplex dorsal root ganglion neuropathic pain sciatic nerve |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122001196 |
| work_keys_str_mv | AT hidetoshikaburagi systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT tetsuyanagata systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT mitsuhiroenomoto systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT takashihirai systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT masakiohyagi systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT kensukeihara systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT kieyoshidatanaka systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT satoeebihara systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT kenasada systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT hiroyukiyokoyama systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT atsushiokawa systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve AT takanoriyokota systemicdnarnaheteroduplexoligonucleotideadministrationforregulatingthegeneexpressionofdorsalrootganglionandsciaticnerve |