MicroRNA compounds and methods for modulating mir-21 activity
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Publication Number
US-12331294-B2
Publication Date
2025-06-17
Expiration Date
Abstract
Described herein are compositions and methods for the inhibition of miR-21 activity. The compositions have certain nucleoside modification patterns that yield potent inhibitors of miR-21 activity. The compositions may be used to inhibit miR-21, and also to treat diseases associated with abnormal expression of miR-21, such as fibrosis and cancer.
Core Innovation
The disclosed invention relates to modified oligonucleotides containing 16 to 19 linked nucleosides, where the nucleobase sequence is complementary to the nucleobase sequence of SEQ ID NO: 1. The modified oligonucleotide includes at least 16 contiguous nucleosides having defined nucleoside pattern II in a 5′ to 3′ orientation, with specific assignments for 2′-O-methoxyethyl nucleosides, S-cEt nucleosides, LNA nucleosides, and β-D-deoxyribonucleosides.
The invention further defines alternative nucleoside patterns for the modified oligonucleotide, also in a 5′ to 3′ orientation. These alternatives constrain how contiguous nucleosides are arranged within the oligonucleotide, including which nucleosides are present as 2′-O-methoxyethyl, S-cEt, LNA, and β-D-deoxyribonucleosides. The nucleobase sequence remains complementary to SEQ ID NO: 1, and the modified oligonucleotides are defined by these pattern-based and nucleoside-type rules.
In addition to pattern and nucleoside identity constraints, the disclosed compounds include refinements such as explicit embodiments involving a nucleobase sequence of SEQ ID NO: 3 and flexibility where each T in SEQ ID NO: 3 is independently a T or U in the oligonucleotide. Further refinements include modified internucleoside linkages, including phosphorothioate internucleoside linkages, and nucleobase modifications such as 5-methylcytosine. The patent context links miR-21 and EMT to metastasis and fibrosis, and positions the modified oligonucleotides as anti-miR-21 compounds for metastasis and organ fibrosis.
Claims Coverage
The independent claim identifies a single compound category with structured nucleoside-pattern constraints and complementarity to SEQ ID NO: 1. The inventive features are then narrowed by dependent claims through specific structural representations (SEQ ID NO: 3), allowed T/U substitutions, nucleoside linkage chemistry, and optional base modification (5-methylcytosine).
Modified oligonucleotide complementary to SEQ ID NO: 1
A compound comprising a modified oligonucleotide consisting of 16 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to the nucleobase sequence of SEQ ID NO: 1.
Sixteen to nineteen nucleoside composition with contiguous nucleoside pattern II rules
The modified oligonucleotide comprises at least 16 contiguous nucleosides of nucleoside pattern II in the 5′ to 3′ orientation, with N_M as a 2′-O-methoxyethyl nucleoside, each N_B as an S-cEt nucleoside, each N_Q as a 2′-O-methoxyethyl nucleoside, and N_Z as a 2′-O-methoxyethyl nucleoside; or corresponding alternatives where N_B is an LNA nucleoside and N_Q is a β-D-deoxyribonucleoside with N_Z as a 2′-O-methoxyethyl nucleoside; or where N_B is an LNA nucleoside, N_Q is a β-D-deoxyribonucleoside, and N_Z is an LNA nucleoside.
Alternative nucleoside pattern rules in the 5′ to 3′ orientation
The modified oligonucleotide comprises one of the following nucleoside patterns in the 5′ to 3′ orientation: (a) N_M-N_B-N_Q-N_Q-N_B-(N_Q-N_Q-N_Q-N_B)_3-N_Q-N_Z; (b) N_B-N_Q-N_Q-N_B-(N_Q-N_Q-N_Q-N_B)_3-N_Q-N_Z; (c) N_Q-N_Q-N_B-(N_Q-N_Q-N_Q-N_B)_3-N_Q-N_Z; or (d) N_Q-N_B-(N_Q-N_Q-N_Q-N_B)_3-N_Q-N_Z, wherein N_M is a 2′-O-methoxyethyl nucleoside, each N_B is an S-cEt nucleoside, each N_Q is a β-D-deoxyribonucleoside, and N_Z is an S-cEt nucleoside.
SEQ ID NO: 3 structural embodiment with base methylation via Me
The compound of claim 1 wherein the modified oligonucleotide structure is selected from structures involving SEQ ID NO: 3 representations, with Me indicating a 5-methyl group on the base.
Modified internucleoside linkage
The compound of claim 1 wherein at least one internucleoside linkage is a modified internucleoside linkage.
Phosphorothioate internucleoside linkage
The compound of claim 11 wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
5-methylcytosine constraint
The compound of claim 1 wherein at least one cytosine is a 5-methylcytosine.
T/U substitution in the SEQ ID NO: 3 nucleobase sequence
The compound of claim 1 wherein the oligonucleotide has the nucleobase sequence of SEQ ID NO: 3, and each T in SEQ ID NO: 3 is independently a T or a U in the oligonucleotide.
Overall, the claims focus on modified oligonucleotides complementary to SEQ ID NO: 1 with defined nucleoside-type and contiguous pattern constraints across 16–19 linked nucleosides, optionally refined by SEQ ID NO: 3 structural representations, allowable T/U substitutions, modified internucleoside linkages including phosphorothioate, and optional 5-methylcytosine base modification.
Stated Advantages
Inhibiting miR-21 activity and de-repressing miR-21-regulated transcripts such as YOD1, PPAR-alpha, RNF167, and SPG20.
Reducing fibrosis-related outcomes, including collagen deposition and collagen1A1 and collagen3A1 expression.
Treating or preventing fibrosis and treating multiple cancer types, including metastasis, with potential reduction in tumor size/number and improved organ function.
Providing diagnostic/biomarker contexts using measures such as ACR, ALT, AST, alpha-fetoprotein, and des-gamma-carboxyprothrombin.
Documented Applications
Treating or preventing fibrosis (including fibroproliferative disorder and fibrosis-associated outcomes such as collagen deposition and collagen1A1/collagen3A1 expression).
Treating cancer types described in the document, including metastasis, with potential outcomes such as reduced tumor size/number.
Diagnostic/biomarker use contexts referenced in the document, including urinary albumin:creatinine ratio (ACR), ALT/AST, alpha-fetoprotein, and des-gamma-carboxyprothrombin.
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