Selective rna-modulating agents
AssigneeUniversity of Massachusetts
InventorsPhillip D. Zamore, Jennifer A. Broderick
Life of this patent
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Abstract
The instant disclosure provides RNA-modulating agents that function to recruit one or more small regulatory RNA molecules (e.g., miRNA molecules, Y RNAs, and siRNAs) to a target mRNA thereby modulating (e.g., inhibiting) the translation of the target mRNA or destabilizing the mRNA. Methods for using the RNA-modulating agents are also provided.
Claims32
An RNA-modulating agent comprising an mRNA binding sequence that is complementary to a portion of a target mRNA sequence, linked to one or more miRNA binding sequences,
- wherein the one or more miRNA binding sequences is complementary to at least positions 2 to 8 of a miRNA from the 5′ end of the miRNA, and
- wherein the miRNA binding sequence comprises at least one modified nucleotide at a nucleotide position that is complementary to any one or more of positions 2, 5, and 8 of the miRNA from the 5′ end of the miRNA.
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A method of modulating the expression of a target mRNA in a subject, the method comprising administering to the subject an effective amount of an RNA-modulating agent, wherein:
- A:
- the target mRNA is a neuromuscular target mRNA,
- the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of the neuromuscular target mRNA, linked to one or more miRNA binding sequences,
- the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of a miRNA, and
- the RNA-modulating agent binds to the neuromuscular target mRNA, thereby modulating the expression of the neuromuscular target mRNA;
- B:
- the target mRNA is in skeletal muscle in the subject,
- the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of the target mRNA, linked to one or more miR-1 binding sequences,
- the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of miR-1, and
- the RNA-modulating agent binds to the target mRNA, thereby modulating the expression of the target mRNA in the skeletal muscle in the subject;
- C:
- the target mRNA is in cardiac muscle in the subject,
- the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of the target mRNA, linked to one or more miR-208 binding sequences,
- the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of miR-208, and
- the RNA-modulating agent binds to the target mRNA, thereby modulating the expression of the target mRNA in the cardiac muscle in the subject;
- D:
- the target mRNA is in kidney in the subject,
- the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of the target mRNA, linked to one or more miR-192 binding sequences,
- the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of miR-192, and
- the RNA-modulating agent binds to the target mRNA, thereby modulating the expression of the target mRNA in the kidney in the subject;
- E:
- the target mRNA is in skin in the subject,
- the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of the target mRNA, linked to one or more miR-203 binding sequences,
- the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of miR-203, and
- the RNA-modulating agent binds to the target mRNA, thereby modulating the expression of the target mRNA in the skin in the subject;
- or
- F:
- the target mRNA is in liver in the subject,
- the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of the target mRNA, linked to one or more miR-122 binding sequences,
- the one or more miRNA binding sequences are complementary to at least positions 2 to 8 of miR-122, and
- the RNA-modulating agent binds to the target mRNA, thereby modulating the expression of the target mRNA in the liver in the subject.
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A method of treating or preventing sarcopenia and/or cachexia in a subject, the method comprising administering to the subject an effective amount of an RNA-modulating agent,
- wherein the RNA-modulating agent comprises an mRNA binding sequence that is complementary to a portion of an activin A mRNA, linked to a miRNA binding sequence,
- wherein the miRNA binding sequence is complementary to at least positions 2 to 8 of a target miRNA, and
- wherein the RNA-modulating agent binds to the activin A mRNA, thereby treating or preventing sarcopenia and/or cachexia in the subject.
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An RNA-modulating agent comprising an mRNA binding sequence that is complementary to a portion of an Activin A mRNA sequence, linked to one or more miRNA binding sequences.
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Dependencies are inferred from the claim text.