Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling.

Amyotrophic Lateral Sclerosis / metabolism Animals Dose-Response Relationship, Drug Female Humans Macaca fascicularis Male Neural Stem Cells / drug effects Neurogenesis / drug effects Oligonucleotides, Antisense / pharmacology Primates Signal Transduction / drug effects Transforming Growth Factor beta / antagonists & inhibitors

Journal

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

ISSN: 1878-7479

Titre abrégé: Neurotherapeutics

Pays: United States

ID NLM: 101290381

Informations de publication

Date de publication:
07 2021

Historique:

accepted: 16 03 2021

pubmed: 17 4 2021

medline: 4 3 2022

entrez: 16 4 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1007/s13311-021-01045-2 PMID: 33860461 PMC: PMC8609055

pubmed: 33860461

doi: 10.1007/s13311-021-01045-2

pii: 10.1007/s13311-021-01045-2

pmc: PMC8609055

doi:

Substances chimiques

Oligonucleotides, Antisense 0

Transforming Growth Factor beta 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1963-1979

Informations de copyright

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