Peters, Sebastian and Kuespert, Sabrina and Wirkert, Eva and Heydn, Rosmarie and Jurek, Benjamin and Johannesen, Siw and Hsam, Ohnmar and Korte, Sven and Ludwig, Florian Timo and Mecklenburg, Lars and Mrowetz, Heike and Altendorfer, Barbara and Poupardin, Rodolphe and Petri, Susanne and Thal, Dietmar R. and Hermann, Andreas and Weishaupt, Jochen H. and Weis, Joachim and Aksoylu, Inci Sevval and Lewandowski, Sebastian A. and Aigner, Ludwig and Bruun, Tim-Henrik and Bogdahn, Ulrich (2021) Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGF beta Signaling. NEUROTHERAPEUTICS, 18 (3). pp. 1963-1979. ISSN 1933-7213, 1878-7479
Full text not available from this repository. (Request a copy)Abstract
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 TGF beta-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGF beta-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX (R) 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 TGF beta-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 TGF beta 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie Biology, Preclinical Medicine > Institut für Anatomie > Lehrstuhl für Molekulare und zelluläre Anatomie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Sep 2022 05:31 |
| Last Modified: | 12 Sep 2022 05:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47037 |
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