Treatment of idiopathic pulmonary fibrosis using RNA complexes that target connective tissue growth factor
Inventors
Lee, Dong Ki • Hong, Sun Woo • Lee, Tae Yeon • Lee, Sae Lo Oom • Kim, Ji Hyun • Na, Yu Ran • Kim, Young-Dong
Assignees
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Publication Number
US-10829761-B2
Publication Date
2020-11-10
Expiration Date
Abstract
In certain aspects, provided herein are RNA complexes (e.g., asymmetric RNA complexes, such as asiRNAs or cell penetrating asiRNAs) that inhibit CTGF expression and are therefore useful for treating idiopathic pulmonary fibrosis.
Core Innovation
The invention provides an RNA complex for treating idiopathic pulmonary fibrosis in a subject diagnosed with idiopathic pulmonary fibrosis. The RNA complex includes an antisense strand of at least 21 nucleotides having sequence complementarity to a connective tissue growth factor (CTGF) mRNA sequence, and a sense strand of 15 to 17 nucleotides having sequence complementarity to the antisense strand. The antisense strand and the sense strand form a complex in which the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end.
The invention further positions a cholesterol moiety attached to the 3′ end of the sense strand. This RNA complex architecture is described with antisense/sense length asymmetry and blunt-end pairing, and it is presented in the context of CTGF mRNA targeting. The partial disclosure also describes CTGF-targeting asymmetric RNA complexes, including cell-penetrating asiRNAs, with chemical modifications that enable cell penetration without transfection or delivery vehicles.
The partial disclosure describes pharmaceutical compositions including the RNA complex with a pharmaceutically acceptable carrier, and lung-directed delivery including inhalation. Functional results in vitro are described as including screening of CTGF-siRNA asiRNAs for CTGF mRNA knockdown in A549 cells, selection of asiRNAs that inhibit CTGF mRNA, and evaluation of modified asiRNAs, including 2′-O-methyl variants, for efficacy and serum nuclease stability. In vivo efficacy is described using a bleomycin-induced lung fibrosis model with intratracheal delivery, with reported reduction of CTGF mRNA and inhibition of fibrosis-related gene/protein expression, including CTGF protein reduction in animal tissues.
Claims Coverage
The independent claim identified is directed to a lung-inhaled therapeutic method for idiopathic pulmonary fibrosis using a CTGF-mRNA-targeting asymmetric RNA complex. The coverage is centered on an antisense/sense length-asymmetric RNA complex with blunt-end pairing and a cholesterol moiety on the sense strand 3′ end.
Lung-inhaled CTGF mRNA-targeting asymmetric RNA complex for IPF
Administering to the lungs of a subject by inhalation an RNA complex comprising an antisense strand of at least 21 nucleotides with sequence complementarity to a CTGF mRNA sequence and a sense strand of 15 to 17 nucleotides with sequence complementarity to the antisense strand, where the antisense 5′ end and sense 3′ end form a blunt end.
Cholesterol moiety at sense strand 3′ end
The RNA complex has a cholesterol moiety attached to the 3′ end of the sense strand.
Across the provided independent claim, the core inventive coverage is an inhaled administration method for idiopathic pulmonary fibrosis using a CTGF mRNA-targeting antisense/sense length-asymmetric RNA complex with blunt-end formation between the antisense 5′ end and sense 3′ end, combined with a cholesterol moiety attached to the sense strand 3′ end.
Stated Advantages
Reduces CTGF mRNA in the bleomycin-induced lung fibrosis model.
Inhibits fibrosis-related gene/protein expression, including fibronectin and collagen type I/III, and reduces CTGF protein in animal tissues.
Enables cell penetration without transfection or delivery vehicles, as described for cell-penetrating asiRNAs.
Provides serum nuclease stability evaluation for modified asiRNAs, including 2′-O-methyl variants.
Documented Applications
Treating idiopathic pulmonary fibrosis by administering the CTGF-targeting RNA complex to the lungs of a subject by inhalation.
Lung-directed delivery in a bleomycin-induced lung fibrosis model using intratracheal delivery, with reported inhibition of fibrosis-related gene/protein expression in animal tissues.
In vitro screening and functional testing of CTGF-siRNA asiRNAs for CTGF mRNA knockdown in A549 cells, including evaluation of modified asiRNAs for efficacy and serum nuclease stability and testing of cell-penetrating asiRNAs for self-delivery and CTGF mRNA/protein inhibition.
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