Aptamer compositions and methods of use thereof
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
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Publication Number
US-10960086-B2
Publication Date
2021-03-30
Expiration Date
Abstract
An aptamer platform capable of efficiently delivering and silencing one, two or more genes in vivo or in vitro is provided. Methods of using the aptamer compositions for selectively targeting cells to down-regulate the expression of multiple genes are also provided.
Core Innovation
The invention relates to an aptamer-siRNA chimera platform for targeted, modular delivery and intracellular RNAi-mediated silencing of multiple genes. The chimera includes first and second ends that comprise aptamers that specifically bind a target protein, with an siRNA construct between the ends. The siRNA construct is processed by cellular RNAi machinery to produce at least two different siRNAs that inhibit expression of two or more different genes in a cell expressing the target protein.
A specific disclosed example focuses on HER family co-targeting using a bivalent aptamer-siRNA arrangement in which an aptamer that binds HER2 is combined with an siRNA construct and an aptamer that binds HER3. Cellular RNAi processing generates active siRNAs that down-regulate EGFR, HER2, and HER3. The reported downstream cellular effects include cell-cycle arrest and apoptosis.
The disclosure further describes asserted improvements associated with the platform, including improved serum stability for the RNAi components using 2′-fluoro modification, enhanced tumor/cell-type targeting using dual aptamers, and in vivo tumor growth suppression in breast cancer xenograft models. The disclosure additionally reports low apparent systemic/innate immune toxicity, including no significant differences in IFNα and IL-6.
Claims Coverage
The provided independent claim covers a pharmaceutical composition defined by specific aptamer sequences at first and second ends and a defined siRNA construct processed by cellular RNAi machinery to produce at least two different siRNAs that inhibit expression of two or more different genes in a cell expressing the target protein. The dependent claims shown narrow the subject and indication, specify the target protein, specify multiple oncogenes to be inhibited, and expand the therapeutic objective to tumor-associated angiogenesis.
Aptamer-siRNA chimera pharmaceutical composition with defined aptamer ends and processed siRNA construct
A pharmaceutical composition comprising an aptamer-siRNA chimera comprising first and second ends comprising an aptamer that specifically binds a target protein, wherein the first end has a nucleic acid sequence according to SEQ ID NO:35 and the second end has a nucleic acid sequence according to SEQ ID NO:36; and an siRNA construct between the first and second ends having a nucleic acid sequence according to SEQ ID NO:37 and SEQ ID NO:38, wherein the siRNA construct is processed by cellular RNAi machinery to produce at least two different siRNAs that specifically inhibit expression of two or more different genes in a cell expressing the target protein.
Reducing tumor burden by administering the chimera composition
A method for reducing tumor burden in a subject by administering an effective amount of the pharmaceutical composition of claim 1.
Breast cancer subject treatment
The method applied to a subject who has breast cancer.
siRNA targeting EGFR as the target protein
The wherein the siRNA targets the EGFR protein as the target protein of the siRNA.
Inhibition of HER2 and HER3 oncogene expression
The aptamers and/or targeting wherein the two or more different genes are HER2 and HER3 oncogenes expressed by the cancer cell.
Reducing tumor-associated angiogenesis by administering the chimera composition
A method for reducing tumor-associated angiogenesis in a subject by administering an effective amount of the pharmaceutical composition of claim 1.
Across the independent claim and the provided dependents, the core claimed concept is an aptamer-siRNA chimera with defined aptamer sequences and a defined siRNA construct that is processed by cellular RNAi machinery to generate at least two siRNAs that inhibit multiple genes in target-expressing cells, with disclosed embodiments directed to reducing tumor burden (including breast cancer) by targeting EGFR and inhibiting HER2 and HER3, and further directed to reducing tumor-associated angiogenesis.
Stated Advantages
Improved serum stability (2′-fluoro modification).
Enhanced tumor/cell-type targeting using dual aptamers.
In vivo tumor growth suppression in breast cancer xenograft models.
Low apparent systemic/innate immune toxicity, with no significant IFNα/IL-6 differences.
Documented Applications
Targeted RNAi-mediated silencing in cells expressing HER family receptors, including co-targeting EGFR, HER2, and HER3, leading to cell-cycle arrest and apoptosis.
Treatment use directed to reducing tumor burden, including in breast cancer subjects.
Reduction of tumor-associated angiogenesis.
In vivo application in breast cancer xenograft models, showing tumor growth suppression.
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