MicroRNAs and methods of their use
Inventors
Saleh, Anthony D. • Van Waes, Carter • Chen, Zhong • Cheng, Hui
Assignees
Mirenlo Inc • Mirecule Inc • US Department of Health and Human Services
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Publication Number
US-11655469-B2
Publication Date
2023-05-23
Expiration Date
2037-03-07
Abstract
Disclosed herein are methods of treating a tumor in a subject, including administering to the subject one or more miRNA nucleic acids or variants (such as mimics or mimetics) thereof with altered expression in the tumor. Also disclosed herein are compositions including one or more miRNA nucleic acids. In some examples, the miRNA nucleic acids are modified miRNAs, for example, and miRNA nucleic acid including one or more modified nucleotides and/or a 5′-end and/or 3′-end modification. In particular examples, the modified miRNA nucleic acid is an miR-30a nucleic acid. Further disclosed herein are methods of diagnosing a subject as having a tumor with altered expression of one or more miRNA nucleic acids. In some embodiments, the methods include detecting expression of one or more miRNAs in a sample from the subject and comparing the expression in the sample from the subject to a control.
Core Innovation
The invention disclosed relates to methods of treating tumors in subjects through the administration of one or more microRNA (miRNA) nucleic acids or their variants, such as mimics or mimetics, which exhibit altered expression in tumors. The compositions may include modified miRNAs with one or more nucleotide modifications and/or 5′-end or 3′-end modifications. Particularly, modified miR-30a nucleic acids are highlighted. The methods also include diagnostic approaches that detect differential expression of miRNAs in subject samples compared to controls, thereby aiding in tumor diagnosis.
The problem being addressed is the deregulation of miRNA expression observed in cancers, including head and neck squamous cell carcinoma (HNSCC). Current therapeutic approaches that target single oncogenes or pathways often face challenges such as intrinsic or acquired resistance. It is unclear which miRNAs co-regulate key mRNA targets involved in the malignant phenotype. Since miRNAs can simultaneously target multiple mRNAs, this invention provides miRNA-based methods and compositions as potential therapeutics to overcome limitations of selective small molecule or biologic therapies and to aid in diagnosis by detecting miRNA expression changes associated with tumors.
Claims Coverage
The patent claims encompass inventive features focused on compositions of miR-30-5p mimic or mimetic nucleic acids with specific chemical modifications and compositions including such mimics encapsulated in delivery systems.
miR-30-5p mimic or mimetic nucleic acid with specific nucleotide modifications
The composition comprises at least one miR-30-5p mimic or mimetic nucleic acid including a guide strand and a passenger strand. The guide strand is about 16 to about 27 nucleotides in length and includes one or more 2′-O-methyl- and/or 2′-fluoro-modified nucleotides between the ninth and nineteenth 5′ residues, when present. Alternatively, the passenger strand of similar length includes such modifications within the three nucleotides at each of its 5′ and 3′ ends and includes a 5′-amino C6 modification. A combination of these modifications on guide and passenger strands is also claimed.
Structural features of the miR-30-5p mimic/mimetic nucleic acid
The mimic or mimetic nucleic acid may include a passenger strand that lacks a 3′ overhang or a guide strand with bases deleted to generate a 3′ overhang. The passenger strand can contain 2′-O-methyl- and/or 2′-fluoro-modifications within the three nucleotides at its 5′ and 3′ ends.
Specific sequences encompassed in the miR-30-5p mimics or mimetics
The composition can comprise miR-30-5p mimics or mimetics corresponding to any of SEQ ID NOs: 37-61, or specific duplexes containing SEQ ID NOs: 42 and 56, 42 and 57, 50 and 61, 73 and 61, or 74 and 61.
Incorporation into delivery systems
The miR-30-5p mimic or mimetic nucleic acid can be incorporated into nanoparticles or liposomes. The liposome may further include targeting molecules specific for tumors, such as an anti-transferrin receptor antibody or fragment thereof.
Pharmaceutical compositions
The compositions may further comprise one or more pharmaceutically acceptable carriers.
Additional modification patterns in miR-30-5p mimic or mimetic
The mimic or mimetic may have a guide strand of about 16 to 27 nucleotides length including 2′-O-methyl-modifications at every even or odd nucleotide position and 2′-fluoro-modifications at complementary positions, combined with a passenger strand containing 2′-O-methyl- and/or 2′-fluoro-modifications within the three terminal nucleotides at each end and a 5′-amino C6 modification.
The claims focus on structurally defined miR-30-5p mimics or mimetics with chemical modifications that improve stability and function, delivered as part of pharmaceutical compositions that can be targeted to tumors, exemplifying therapeutic nucleic acid compositions for cancer treatment.
Stated Advantages
miRNA-based therapeutics may help overcome intrinsic or acquired resistance associated with therapies targeting a single oncogene or pathway in cancer.
Modified miRNAs have improved nuclease resistance and enhanced stability, leading to increased half-life and efficacy.
The disclosed synthetic miR-30a-5p mimic formulations can delay tumor growth in xenograft tumor models of HNSCC.
miR-30a-5p expression inhibits cancer cell proliferation, motility, invasion, and enhances chemosensitivity.
Documented Applications
Treatment of tumors, including squamous cell carcinoma such as head and neck squamous cell carcinoma (HNSCC).
Diagnosis of tumors by detecting altered expression of one or more miRNAs in subject samples compared to normal controls.
Administration of miR-30-5p mimics or mimetics to inhibit tumor growth and proliferation in vivo in xenograft models.
Use in combination therapies with chemotherapeutic agents such as cisplatin for improved treatment efficacy.
Potential treatment of a broad variety of cancers explicitly including but not limited to cervical squamous cell carcinoma, lung squamous cell carcinoma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, and pancreatic carcinoma.
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