Kuespert, Sabrina and Heydn, Rosmarie and Peters, Sebastian and Wirkert, Eva and Meyer, Anne-Louise and Sieboerger, Mareile and Johannesen, Siw and Aigner, Ludwig and Bogdahn, Ulrich and Bruun, Tim-Henrik (2020) Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2-A Key Single Gene Target for Safe and Effective Inhibition of TGF beta Signaling. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21 (6): 1952. ISSN , 1422-0067
Full text not available from this repository. (Request a copy)Abstract
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 TGF beta 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 TGF beta signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGF beta 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 TGF beta signaling related disorders.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR-BETA; NUSINERSEN; DELIVERY; THERAPY; PHASE-1; TGF beta signaling; TGFBR2; antisense oligonucleotide; drug development; therapeutic frontiers |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Mar 2021 10:13 |
| Last Modified: | 29 Mar 2021 10:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44982 |
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