| Autor: |
Maurizio Chioccioli, Subhadeep Roy, Rachel Newell, Linda Pestano, Brent Dickinson, Kevin Rigby, Jose Herazo-Maya, Gisli Jenkins, Steward Ian, Gauri Saini, Simon R. Johnson, Rebecca Braybrooke, Guying Yu, Maor Sauler, Farida Ahangari, Shuizi Ding, Joseph DeIuliis, Nachelle Aurelien, Rusty L. Montgomery, Naftali Kaminski |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
EBioMedicine, Vol 85, Iss , Pp 104304- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2352-3964 |
| DOI: |
10.1016/j.ebiom.2022.104304 |
| Popis: |
Summary: Background: MicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported that systemically delivered miR-29 mimic MRG-201 reduced fibrosis in animal models, supporting the consideration of miR-29-based therapies for idiopathic pulmonary fibrosis (IPF). Methods: We generated MRG-229, a next-generation miR-29 mimic based on MRG-201 with improved chemical stability due to additional sugar modifications and conjugation with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide)1. We investigated the anti-fibrotic efficacy of MRG-229 on TGF-β1 treated human lung fibroblasts (NHLFs), human precision cut lung slices (hPCLS), and in vivo bleomycin studies; toxicology was assessed in two animal models, rats, and non-human primates. Finally, we examined miR-29b levels in a cohort of 46 and 213 patients with IPF diagnosis recruited from Yale and Nottingham Universities (Profile Cohort), respectively. Findings: The peptide-conjugated MRG-229 mimic decreased expression of pro-fibrotic genes and reduced collagen production in each model. In bleomycin-treated mice, the peptide-conjugated MRG-229 mimic downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, the peptide-conjugated MRG-229 mimic was well tolerated at clinically relevant doses with no adverse findings observed. In human peripheral blood from IPF patients decreased miR-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment. Interpretation: Collectively, our results provide support for the development of the peptide-conjugated MRG-229 mimic as a potential therapy in humans with IPF. Funding: This work was supported by NIH NHLBI grants UH3HL123886, R01HL127349, R01HL141852, U01HL145567. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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