Nucleic acid drug targeting MURF1
Inventors
Fujiwara, Takahiro • Tomita, Kazuyoshi • NASHIKI, Kunitaka • NAGASAWA, Ayumi • Yoshimoto, Ryo • Ito, Takahito
Assignees
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Publication Number
US-12584132-B2
Publication Date
2026-03-24
Expiration Date
Abstract
It was found that nucleic acids for the specific targeting sequences or nucleic acids having the specific sequences have superior suppression activities of MURF1 expression. Pharmaceutical compositions including the nucleic acids as active ingredient are useful for treating or preventing disease accompanied by one or more symptoms selected from the group consisting of decrease in muscle mass, decrease in muscle strength and muscle dysfunction.
Core Innovation
The invention relates to nucleic-acid medicines for suppressing the expression of MURF1 (muscle RING finger 1). The problem addressed is muscle-atrophy-associated diseases characterized by decrease in muscle mass, decrease in muscle strength, and muscle dysfunction. The nucleic acids are directed to MURF1 mRNA using defined target regions in SEQ ID NO:609.
Specific oligonucleotides are defined as 15 to 30 nucleotides that have at least 15 bases or more complementary to the base sequence consisting of positions 1427 to 1447 of SEQ ID NO:609, and additional target regions are described for MURF1 mRNA, including 188–229, 1039–1060, 1427–1447, 1510–1530, and 1715–1737. Complementary or substantially complementary sequences are included, and numerous example oligonucleotides are provided, including a positive control.
Preferred oligonucleotide modalities include siRNA, antisense oligonucleotide, shRNA, and miRNA, including double-stranded nucleic-acid forms and, for siRNA embodiments, optional 3′ end overhangs. The document characterizes the nucleic acids by demonstrating suppression of MURF1 expression in in vitro settings using RT-PCR/real-time PCR-based evaluations, and it describes pharmaceutical composition suitability and safety/usefulness in connection with the claimed nucleic acids.
Claims Coverage
The independent claims cover MURF1-suppressing nucleic acids defined by target complementarity, SEQ ID-based base sequences, double-stranded nucleic-acid combinations, and modality limitations. Across the independent claims, the inventive features focus on defined MURF1 mRNA regions, sequence length/identity constraints, limited sequence edits, and optional siRNA 3′ end overhangs.
Sequence length and complementarity to MURF1 target positions
An oligonucleotide consisting of 15 to 30 nucleotides having at least 15 bases or more complementary to the base sequence consisting of positions 1427 to 1447 of SEQ ID NO: 609, suppressing the expression of MURF1.
Consecutive-base requirement within a specified base sequence
The nucleic acid comprising at least 15 consecutive bases corresponding to SEQ ID NO: 621, as a refinement of the nucleic acid suppressing MURF1 expression.
Specified nucleic-acid modality for suppressing MURF1 expression
Suppressing the expression of MURF1 using a nucleic acid selected from siRNA, antisense oligonucleotide, shRNA, or miRNA.
siRNA with 3′ end overhangs on sense and/or antisense strand
The nucleic acid is siRNA that has overhangs at the 3′ end of the sense and/or antisense strand.
Defined SEQ ID base sequences with limited sequence edits
A nucleic acid comprising the base sequence of SEQ ID NO: 482 or 484, including wherein the base sequence of SEQ ID NO: 482 has 1 to 3 bases deleted, substituted or inserted at positions 2 to 18, or wherein the base sequence of SEQ ID NO: 484 has 1 to 3 bases deleted, substituted or inserted, and suppressing the expression of MURF1.
Double-stranded nucleic-acid sequence combinations using specified SEQ ID pairs
A double-stranded nucleic acid comprising combinations of oligonucleotides: an oligonucleotide consisting of the base sequence of SEQ ID NO: 481 or 636 and an oligonucleotide consisting of the base sequence of SEQ ID NO: 482, or an oligonucleotide consisting of the base sequence of SEQ ID NO: 483 or 637 and an oligonucleotide consisting of the base sequence of SEQ ID NO: 484.
Double-stranded siRNA with 3′-end overhang placement
The double-stranded nucleic acid is an siRNA having 3′-end overhangs on the sense and/or antisense strand.
Overall, the claim set covers MURF1-suppressing nucleic acids defined by target complementarity, SEQ ID-based base sequences with limited 1–3 base edits, and double-stranded nucleic-acid constructions using defined SEQ ID pair combinations, with refinements specifying siRNA, antisense oligonucleotide, shRNA, or miRNA modalities and, for siRNA, optional 3′ end overhang features.
Stated Advantages
Superior knockdown.
Suitable for pharmaceuticals.
Documented Applications
Treating or preventing muscle-atrophy-associated diseases associated with decreased muscle mass, decreased muscle strength, and muscle dysfunction using nucleic-acid suppression of MURF1 expression.
In vitro evaluation of MURF1 expression suppression using mouse B16 and human skeletal myoblast cells, assessed by RT-PCR/real-time PCR.
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