Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling
Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Rece...
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| Veröffentlicht in: | Neurotherapeutics 2021-07, Vol.18 (3), p.1963-1979 |
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| creator | Peters, Sebastian Kuespert, Sabrina Wirkert, Eva Heydn, Rosmarie Jurek, Benjamin Johannesen, Siw Hsam, Ohnmar Korte, Sven Ludwig, Florian Timo Mecklenburg, Lars Mrowetz, Heike Altendorfer, Barbara Poupardin, Rodolphe Petri, Susanne Thal, Dietmar R. Hermann, Andreas Weishaupt, Jochen H. Weis, Joachim Aksoylu, Inci Sevval Lewandowski, Sebastian A. Aigner, Ludwig Bruun, Tim-Henrik Bogdahn, Ulrich |
| description | Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells)
in vitro
. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein
in vivo
. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time
in vitro
and
in vivo
evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis. |
| doi_str_mv | 10.1007/s13311-021-01045-2 |
| format | Article |
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in vitro
. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein
in vivo
. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time
in vitro
and
in vivo
evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.</description><identifier>ISSN: 1933-7213</identifier><identifier>ISSN: 1878-7479</identifier><identifier>EISSN: 1878-7479</identifier><identifier>DOI: 10.1007/s13311-021-01045-2</identifier><identifier>PMID: 33860461</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>1-Phosphatidylinositol 3-kinase ; Aging ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - metabolism ; Animals ; Antisense oligonucleotides ; Biomedical and Life Sciences ; Biomedicine ; Cell differentiation ; Dose-Response Relationship, Drug ; Epigenetics ; Farmakologi och toxikologi ; Female ; Humans ; Macaca fascicularis ; Male ; MAP kinase ; Medicin och hälsovetenskap ; Medicinska och farmaceutiska grundvetenskaper ; Neural stem cells ; Neural Stem Cells - drug effects ; Neural Stem Cells - metabolism ; Neurobiology ; Neurodegeneration ; Neurodegenerative diseases ; Neurogenesis ; Neurogenesis - drug effects ; Neurogenesis - physiology ; Neurology ; Neurosciences ; Neurosurgery ; Neurovetenskaper ; Oligonucleotides, Antisense - pharmacology ; Original ; Original Article ; Primates ; Progenitor cells ; Regeneration ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Subventricular zone ; Toxicity ; Transcription factors ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming Growth Factor beta - biosynthesis</subject><ispartof>Neurotherapeutics, 2021-07, Vol.18 (3), p.1963-1979</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells)
in vitro
. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein
in vivo
. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time
in vitro
and
in vivo
evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Aging</subject><subject>Amyotrophic lateral sclerosis</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Animals</subject><subject>Antisense oligonucleotides</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell differentiation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epigenetics</subject><subject>Farmakologi och toxikologi</subject><subject>Female</subject><subject>Humans</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>Neural stem cells</subject><subject>Neural Stem Cells - drug effects</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neurobiology</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurogenesis</subject><subject>Neurogenesis - drug effects</subject><subject>Neurogenesis - physiology</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Neurosurgery</subject><subject>Neurovetenskaper</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Original</subject><subject>Original Article</subject><subject>Primates</subject><subject>Progenitor cells</subject><subject>Regeneration</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Subventricular zone</subject><subject>Toxicity</subject><subject>Transcription factors</subject><subject>Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Transforming Growth Factor beta - 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Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells)
in vitro
. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein
in vivo
. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time
in vitro
and
in vivo
evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>33860461</pmid><doi>10.1007/s13311-021-01045-2</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-0826-7482</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1933-7213 |
| ispartof | Neurotherapeutics, 2021-07, Vol.18 (3), p.1963-1979 |
| issn | 1933-7213 1878-7479 1878-7479 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_462746 |
| source | MEDLINE; SWEPUB Freely available online; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection; SpringerLink Journals - AutoHoldings |
| subjects | 1-Phosphatidylinositol 3-kinase Aging Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - metabolism Animals Antisense oligonucleotides Biomedical and Life Sciences Biomedicine Cell differentiation Dose-Response Relationship, Drug Epigenetics Farmakologi och toxikologi Female Humans Macaca fascicularis Male MAP kinase Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper Neural stem cells Neural Stem Cells - drug effects Neural Stem Cells - metabolism Neurobiology Neurodegeneration Neurodegenerative diseases Neurogenesis Neurogenesis - drug effects Neurogenesis - physiology Neurology Neurosciences Neurosurgery Neurovetenskaper Oligonucleotides, Antisense - pharmacology Original Original Article Primates Progenitor cells Regeneration Signal Transduction - drug effects Signal Transduction - physiology Subventricular zone Toxicity Transcription factors Transforming Growth Factor beta - antagonists & inhibitors Transforming Growth Factor beta - biosynthesis |
| title | Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T02%3A43%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Reconditioning%20the%20Neurogenic%20Niche%20of%20Adult%20Non-human%20Primates%20by%20Antisense%20Oligonucleotide-Mediated%20Attenuation%20of%20TGF%CE%B2%20Signaling&rft.jtitle=Neurotherapeutics&rft.au=Peters,%20Sebastian&rft.date=2021-07-01&rft.volume=18&rft.issue=3&rft.spage=1963&rft.epage=1979&rft.pages=1963-1979&rft.issn=1933-7213&rft.eissn=1878-7479&rft_id=info:doi/10.1007/s13311-021-01045-2&rft_dat=%3Cproquest_swepu%3E2600516901%3C/proquest_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2600516901&rft_id=info:pmid/33860461&rfr_iscdi=true |