Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction

Senatorov, Vladimir V.; Friedman, Aaron R.; Milikovsky, Dan Z.; Ofer, Jonathan; Saar‐Ashkenazy, Rotem; Charbash, Adiel; Jahan, Naznin; Chin, Gregory T.; Mihaly, Eszter; Lin, Jessica May; Ramsay, Harrison; Moghbel, Ariana; Preininger, Marcela K.; Eddings, Chelsy R.; Harrison, Helen V.; Patel, Rishi; Shen, Yishuo; Ghanim, Hana Y.; Sheng, Huanjie; Veksler, Ronel; Sudmant, Peter H.; Becker, Albert; Hart, Barry; Rogawski, Michael A.; Dillin, Andrew; Friedman, Alon; Kaufer, Daniela

doi:10.1126/scitranslmed.aaw8283

Cited by 195 publications

(193 citation statements)

References 106 publications

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“…TGFBR1 only recognizes ligands bound to TGFBR2 but not ligands that are free in solution [50]. Proteins of the TGFβ family appear to be involved in various physiological and pathophysiological processes e.g., in the brain: increased TGFβ levels mediated by activation of TGFBR2 inhibit neurogenesis and may thus favor ageing and neurodegeneration [12,51,52]. In addition, TGFBR2 is an important TGFβ-mediator to ensure organ elasticity and plasticity by mechanical modifications of extracellular matrix and angio-or vasculogenesis, for example.…”

Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFβ receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFβ signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFβ signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFβ signaling related disorders.

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Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Kuespert

Heydn

Peters

et al. 2020

IJMS

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“…In parenchymal cells, a prominent upregulation of GFAP indicated the activation of astrocytes, in line with the nding that GFAP concentrations are elevated in the blood of COVID-19 patients 56 . An increased BBB permeability and astrocyte activation may cause epileptic seizures in COVID-19 patients as in incontinentia pigmenti 54,55,57 . wells/group; representative for 3 independent experiments).…”

Section: Discussionmentioning

confidence: 99%

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Wenzel¹,

Lampe²,

Mueler-Fielitz³

et al. 2020

Preprint

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Several lines of evidence suggest that neurological symptoms in COVID-19 patients are partially due to damage to small vessels. However, the potential mechanisms are unclear. Here, we show that brain endothelial cells express SARS-CoV-2 receptors. The main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of NF-κB signaling. By ablating NEMO, Mpro induces the death of human brain endothelial cells and a microvascular pathology in mice that is similar to what we find in the brain of COVID-19 patients. Importantly, the inhibition of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Our data suggest RIPK as a therapeutic target to treat the neuropathology of COVID-19.

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“…The fourth option is IPW-5371, a small molecule blocking the transforming growth factor β receptor (TGFβR) signaling. In a recent study (Senatorov et al, 2019), IPW reduced hyperexcitability in a mouse model, protecting BBB functions. The activated protein C (APC) therapeutic analog 3K3A-APC is a fifth option.…”

Section: Bbb Repairing Pharmacology: Available Optionsmentioning

confidence: 92%

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

Giannoni

Claeysen

Noè

et al. 2020

Front. Aging Neurosci.

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A bidirectional crosstalk between peripheral players of immunity and the central nervous system (CNS) exists. Hence, blood-brain barrier (BBB) breakdown is emerging as a participant mechanism of dysregulated peripheral-CNS interplay, promoting diseases. Here, we examine the implication of BBB damage in neurodegeneration, linking it to peripheral brain-directed autoantibodies and gut-brain axis mechanisms. As BBB breakdown is a factor contributing to, or even anticipating, neuronal dysfunction(s), we here identify contemporary pharmacological strategies that could be exploited to repair the BBB in disease conditions. Developing neurovascular, add on, therapeutic strategies may lead to a more efficacious pre-clinical to clinical transition with the goal of curbing the progression of neurodegeneration.

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Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction

Cited by 195 publications

References 106 publications

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

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