RNA interference in dermal and fibrotic indications
Inventors
Khvorova, Anastasia • Salomon, William • Kamens, Joanne • Samarsky, Dmitry • Woolf, Tod M. • PAVCO, PAMELA A. • Libertine, Lyn • Cardia, James • Bulock, Karen G.
Assignees
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Publication Number
US-10913948-B2
Publication Date
2021-02-09
Expiration Date
Abstract
The present invention relates to RNAi constructs with improved tissue and cellular uptake characteristics and methods of use of these compounds in dermal and fibrotic applications.
Core Innovation
The invention relates to a double-stranded ribonucleic acid (dsRNA) comprising a sense strand and an antisense strand, where the dsRNA is an sd-rxRNA. The sd-rxRNA includes a double-stranded region and a single-stranded region at the 3′ end of the antisense strand, and the sense strand and/or antisense strand comprise at least 12 contiguous nucleotides of a sequence selected from the listed SEQ ID NOs. The antisense strand is 16-23 nucleotides long and the sense strand is 8-15 nucleotides long.
The single-stranded region contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications, and at least 40% of the nucleotides of the double-stranded nucleic acid molecule are modified. The dsRNA is optionally hydrophobically modified or linked to a hydrophobic conjugate. The compositions are described as suitable for skin delivery, including topical delivery or intradermal injection.
The patent also describes hydrophobic modifications and hydrophobic conjugates for nucleic acids, including hydrophobic moieties such as cholesterol and other steroids, sterols, and lipophilic vitamins, in nucleic-acid conjugate architectures with defined linkage concepts. The document further links the sd-rxRNA constructs and delivery/formulation strategies to therapeutic contexts associated with skin scarring/fibrosis and other fibrotic disorders.
Claims Coverage
The claim coverage centers on one sd-rxRNA dsRNA architecture defined by sequence selection, strand-length ranges, a double-stranded region plus a 3′-end single-stranded region on the antisense strand, and phosphorothioate modification constraints. Dependent claims further add hydrophobic modification or hydrophobic conjugation, a neutral skin-delivery composition, and treatment or prevention of fibrotic disorders.
Sequence-defined sd-rxRNA with defined sense and antisense regions
A double-stranded ribonucleic acid (dsRNA) comprising a sense strand and an antisense strand, wherein the dsRNA is an sd-rxRNA; the antisense strand is 16-23 nucleotides long and the sense strand is 8-15 nucleotides long; the sd-rxRNA includes a double-stranded region and a single-stranded region; the double-stranded region is 8-15 nucleotides long; and the single-stranded region is at the 3′ end of the antisense strand and is 4-12 nucleotides long.
Sequence selection from defined SEQ ID NOs
The sense strand and/or antisense strand comprises at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOs 4309, 4310, 4311, 4312, 4313, 4314, 4315, 4316, 4317, 4318, 4319, 501, 502, and 1059.
Phosphorothioate modification pattern and overall modification threshold
The single-stranded region contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications, and at least 40% of the nucleotides of the double-stranded nucleic acid molecule are modified.
Hydrophobic modification or hydrophobic conjugation of dsRNA
The dsRNA is either hydrophobically modified or linked to a hydrophobic conjugate.
Neutral skin-delivery formulation for topical or intradermal use
A skin-delivery formulation that is neutral and suitable for topical delivery or intradermal injection.
Administering dsRNA to the skin
A method wherein the dsRNA is administered to the skin of a subject in need thereof.
Treating or preventing a fibrotic disorder
A method of using the dsRNA to treat or prevent a fibrotic disorder.
Selected fibrotic disorders
The fibrotic disorder is selected from pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulonephritis, liver fibrosis, skin fibrosis, muscle fibrosis, radiation fibrosis, kidney fibrosis, proliferative vitreoretinopathy, restenosis, uterine fibrosis, or scarring that causes failure of a trabeculectomy.
Overall claim coverage centers on an sd-rxRNA dsRNA with defined sense and antisense length ranges, a double-stranded region plus a 3′-end single-stranded antisense region, selectable sequence options, and extensive phosphorothioate modification requirements including an overall modification threshold. The coverage is further narrowed by hydrophobic modification or hydrophobic conjugation and by skin-delivery formulation and administration for treating or preventing selected fibrotic disorders.
Stated Advantages
Not explicitly described in patent.
Documented Applications
The document reports gene-expression inhibition data for targets including CTGF, SPP1, and PTGS2 using sd-rxRNA or sd-rxRNA-like oligonucleotides, with measurements in cells including A549 and PC-3.
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