Author: Saini, Gauri ; Newell, Rachel ; Pestano, Linda ; Sauler, Maor ; Chioccioli, Maurizio ; Ian, Steward ; Ahangari, Farida ; Montgomery, Rusty L ; Johnson, Simon R ; DeIuliis, Joseph ; Yu, Guying ; Dickinson, Brent ; Rigby, Kevin ; Braybrooke, Rebecca ; Roy, Subhadeep ; Kaminski, Naftali ; Jenkins, Gisli ; Herazo-Maya, Jose ; Ding, Shuizi ; Aurelien, Nachelle

BACKGROUNDMicroRNAs 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).METHODSWe 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.FINDINGSThe 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.INTERPRETATIONCollectively, our results provide support for the development of the peptide-conjugated MRG-229 mimic as a potential therapy in humans with IPF.FUNDINGThis work was supported by NIH NHLBI grants UH3HL123886, R01HL127349, R01HL141852, U01HL145567.

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Indication	Highest Phase	Country/Location	Organization	Date
Idiopathic Pulmonary Fibrosis	Preclinical	US	Viridian Therapeutics, Inc.	-

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