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

Neurotherapeutics, vol. 18, pp. 1963–1979

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 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.

Authors 23

1. Sebastian Peters

   University Hospital Regensburg

   Affiliation as printed

   Department of Neurology, University Hospital Regensburg, Regensburg, Germany

   Velvio GmbH, Am Biopark 11, Regensburg, Germany

2. Sabrina Kuespert

   University Hospital Regensburg

   Affiliation as printed

   Department of Neurology, University Hospital Regensburg, Regensburg, Germany

   Velvio GmbH, Am Biopark 11, Regensburg, Germany

3. Eva Wirkert

   University Hospital Regensburg

   Affiliation as printed

   Department of Neurology, University Hospital Regensburg, Regensburg, Germany

   Velvio GmbH, Am Biopark 11, Regensburg, Germany

4. Rosmarie Heydn

   University Hospital Regensburg

   Affiliation as printed

   Department of Neurology, University Hospital Regensburg, Regensburg, Germany

   Velvio GmbH, Am Biopark 11, Regensburg, Germany

5. Benjamin Jurek

   University of Regensburg

   Affiliation as printed

   Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany

6. Siw Wollebæk Johannesen

   University Hospital Regensburg

   Affiliation as printed

   Department of Neurology, University Hospital Regensburg, Regensburg, Germany

   Velvio GmbH, Am Biopark 11, Regensburg, Germany

7. Ohnmar Hsam

   University Hospital Regensburg

   Affiliation as printed

   Department of Neurology, University Hospital Regensburg, Regensburg, Germany

8. Sven Korte

   Covance (Germany)

   Affiliation as printed

   Covance Preclinical Services GmbH, Muenster, Germany

9. Florian Timo Ludwig

   Covance (Germany)

   Affiliation as printed

   Covance Preclinical Services GmbH, Muenster, Germany

10. Lars Mecklenburg

    Covance (Germany)

    Affiliation as printed

    Covance Preclinical Services GmbH, Muenster, Germany

11. Heike Mrowetz

    Paracelsus Medical University

    Affiliation as printed

    Institute of Experimental and Clinical Cell Therapy, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

    Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

12. Barbara Altendorfer

    Paracelsus Medical University

    Affiliation as printed

    Institute of Experimental and Clinical Cell Therapy, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

    Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

13. Rodolphe Poupardin

    Paracelsus Medical University

    Affiliation as printed

    Institute of Experimental and Clinical Cell Therapy, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

14. Susanne Petri

    Medizinische Hochschule Hannover

    Affiliation as printed

    Department of Neurology, University Hospital MHH, Hannover, Germany

15. Dietmar Rudolf Thal

    KU Leuven · Universität Ulm

    Affiliation as printed

    Department for Imaging and Pathology, Laboratory for Neuropathology, University of Leuven, Leuven, Belgium

    Laboratory of Neuropathology, Institute of Pathology, Ulm University, Ulm, Germany

16. Andreas Hermann

    German Center for Neurodegenerative Diseases · University of Rostock · Universitätsmedizin Rostock

    Affiliation as printed

    Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, and German Center for Neurodegenerative Diseases (DZNE) Rostock, Rostock, Germany

17. Jochen Hans Weishaupt

    University Medical Centre Mannheim

    Affiliation as printed

    Department of Neurology, University Hospital Mannheim, Mannheim, Germany

18. Joachim Weis Aachen Institute of Neuropathology

    RWTH Aachen University

    Affiliation as printed

    Institute of Neuropathology, RWTH Aachen University Medical School, Aachen, Germany

19. Inci Sevval Aksoylu

    Karolinska Institutet

    Affiliation as printed

    Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden

20. Sebastian A. Lewandowski

    KTH Royal Institute of Technology · Karolinska Institutet · Science for Life Laboratory

    Affiliation as printed

    Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden

    SciLifeLab, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden

21. Ludwig Aigner

    Paracelsus Medical University

    Affiliation as printed

    Institute of Experimental and Clinical Cell Therapy, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

    Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria

22. Tim‐Henrik Bruun

    University Hospital Regensburg

    Affiliation as printed

    Department of Neurology, University Hospital Regensburg, Regensburg, Germany

    Velvio GmbH, Am Biopark 11, Regensburg, Germany

23. Ulrich Bogdahn corresponding

    University Hospital Regensburg · Paracelsus Medical University

    Affiliation as printed

    Department of Neurology, University Hospital Regensburg, Regensburg, Germany. uli.bogdahn@ukr.de

    Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria. uli.bogdahn@ukr.de

    Velvio GmbH, Am Biopark 11, Regensburg, Germany. uli.bogdahn@ukr.de

    Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria