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

Neurotherapeutics, 2021 · DOI: https://doi.org/10.1007/s13311-021-01045-2 · Published: April 15, 2021

Neurology Genetics Regenerative Medicine & Stem Cells

Simple Explanation

This study introduces a novel antisense oligonucleotide (NVP-13) that targets TGFβ-RII, a protein involved in regulating cell growth and differentiation. Reducing TGFβ-RII expression can promote neurogenesis, the formation of new neurons in the brain. The researchers tested NVP-13 in vitro on human neuronal precursor cells and in vivo by injecting it into cynomolgus monkeys. They observed that NVP-13 effectively reduced TGFβ-RII expression and enhanced neurogenesis in the hippocampus and subventricular zone of the monkeys' brains. These findings suggest that NVP-13 could be a potential therapeutic approach for treating neurodegenerative disorders by modulating neurogenesis.

Study Duration

13 Weeks

Participants

Male and female cynomolgus monkeys

Evidence Level

Not specified

Key Findings

1
NVP-13 significantly downregulated TGFβ-RII mRNA and protein expression in vitro in human neural precursor cells.
2
In vivo, NVP-13 reduced TGFβRII target expression by nearly 50% in the spinal cord, subventricular zone (SVZ), and hippocampus of cynomolgus monkeys.
3
NVP-13 treatment upregulated neurogenic niche activity, enhancing the expression of neural stem cell markers (Sox-2, Msi-1) and differentiation markers (DCX, Glypican) in the monkeys' brains.

Research Summary

The study investigates the potential of a novel antisense oligonucleotide (NVP-13) to recondition the neurogenic niche in adult non-human primates by attenuating TGFβ signaling. NVP-13 effectively downregulates TGFβ-RII expression both in vitro and in vivo, leading to the modulation of intracellular fibrosis and stem cell niche markers. The findings suggest that NVP-13 can recover the neurogenic niche by downregulating TGFβ signaling, potentially offering a translatable approach for treating neurodegenerative disorders.

Practical Implications

Therapeutic Potential

NVP-13 may serve as a novel therapeutic agent for neurodegenerative diseases, such as ALS, by promoting neurogenesis.

Biomarker Development

Glypican could be a promising clinical biomarker for monitoring neurogenesis in future clinical trials.

Drug Dosage Optimization

The study suggests that lower doses of NVP-13 (e.g., 1 mg) may be more effective in activating neural precursors in the adult neurogenic niche, warranting further investigation in clinical settings.

Study Limitations

1
NVP-13 is specific to human and non-human primate mRNA sequences, limiting its use in current ALS animal models.
2
The study could not investigate the same areas of pathology in human patients with ALS and in the monkeys.
3
Morphological analysis in specific areas like the spinal cord was limited due to regulatory study program issues within the GLP-Tox study.

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