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

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-...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-03, Vol.21 (6), p.1952
Main Authors: Kuespert, Sabrina, Heydn, Rosmarie, Peters, Sebastian, Wirkert, Eva, Meyer, Anne-Louise, Siebörger, Mareile, Johannesen, Siw, Aigner, Ludwig, Bogdahn, Ulrich, Bruun, Tim-Henrik
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
antisense oligonucleotide
Antisense oligonucleotides
Attenuation
Autophagy
Biocompatibility
Candidates
Cell lines
Design
Drug delivery systems
Drug development
Drug dosages
Fibrosis
Gene expression
Genetic modification
Lead compounds
Lung diseases
Monkeys & apes
mRNA
Neural stem cells
Neurodegeneration
Proteins
Stem cells
tgfbr2
tgfβ signaling
therapeutic frontiers
Toxicity
Transfection
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Summary: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 -design, transfection, and gymnotic delivery of small batch syntheses. Primary and 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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21061952