Bivalent siRNA chimeras and methods of use thereof
Inventors
Assignees
Augusta University • Augusta University Research Institute Inc
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10689654-B2
Publication Date
2020-06-23
Expiration Date
Abstract
A bivalent siRNA chimera platform capable of efficiently delivering and silencing two or more genes in vivo or in vitro is provided. Methods of using the bivalent siRNA chimeras for selectively targeting cells to down-regulate the expression of multiple genes are also provided.
Core Innovation
The invention relates to a bivalent aptamer-siRNA chimera platform. The chimera comprises first and second ends, where each end comprises an aptamer that specifically binds a target protein, and an siRNA construct between the ends.
The siRNA construct is processed by cellular RNAi machinery to produce at least two different siRNAs. The produced siRNAs specifically inhibit expression of two or more different genes in a cell expressing the target protein, including survivin and EGFR in particular examples, with PSMA as a target protein in particular examples.
The platform is described as enabling selective delivery and simultaneous silencing of multiple genes. The described approach is further associated with inducing or promoting apoptosis and suppressing tumor growth and tumor-associated angiogenesis, including reduced VEGF-A and reduced CD31+ microvessels.
Additional described attributes include targeting scope where aptamers bind tumor/viral cell surface proteins or secreted microenvironment proteins, while the siRNAs target oncogenes or viral genes. The document also describes use as pharmaceutical compositions and provides sequence identity references to specific SEQ ID Nos.
Claims Coverage
The partial content identifies one independent chimera claim and six independent method claims, yielding a set of inventive features centered on a bivalent aptamer-siRNA chimera with RNAi processing to generate multiple siRNAs targeting multiple genes. The inventive features are defined at the chimera level and then carried into method contexts for killing cancer cells, reducing tumor burden, reducing tumor-associated angiogenesis, and treating viral infection.
Bivalent aptamer-siRNA chimera producing multiple siRNAs for multi-gene inhibition
A bivalent aptamer-siRNA chimera comprising first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a target protein; and an siRNA construct between the first and second ends, 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.
Administering bivalent aptamer-siRNA chimera to induce or promote apoptosis by aptamer-targeted multi-gene inhibition
A method for killing cancer cells in a subject comprising administering an effective amount of a bivalent siRNA chimera to induce or promote apoptosis of the cancer cells, wherein the bivalent siRNA chimera comprises first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a cell surface protein expressed by the cancer cells; and an siRNA construct between the first and second ends, wherein the siRNA construct is processed by cellular RNAi machinery of the cancer cells to produce at least two different siRNAs that specifically inhibit expression of two or more different genes in the cancer cells to promote apoptosis of the cancer cells.
Reducing tumor burden by administering bivalent aptamer-siRNA chimera to promote apoptosis
A method for reducing tumor burden in a subject in need thereof comprising administering to the subject an effective amount of a bivalent siRNA chimera to induce or promote apoptosis of the tumor cells, wherein the bivalent siRNA chimera comprises first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a cell surface protein expressed by the tumor cells; and an siRNA construct between the first and second ends, wherein the siRNA construct is processed by cellular RNAi machinery of the cancer cells to produce at least two different siRNAs that specifically inhibit expression of two or more different genes in the tumor cells to promote apoptosis of the tumor cells and thereby reduce tumor burden in the subject.
Reducing tumor associated angiogenesis using bivalent aptamer-siRNA chimera with EGFR and survivin gene inhibition
A method of reducing tumor associated angiogenesis in a subject in need thereof comprising administering to the subject an effective amount of a bivalent siRNA chimera to reduce tumor associated angiogenesis, wherein the bivalent siRNA chimera comprises first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a cell surface protein expressed by the tumor; and an siRNA construct between the first and second ends, wherein the siRNA construct is processed by cellular RNAi machinery of tumor to produce at least two different siRNAs that specifically inhibit expression of two or more different genes in the tumor, wherein the two or more different genes comprise EGFR and survivin.
Treating viral infection by administering bivalent aptamer-siRNA chimera targeting cell surface viral proteins and multiple viral genes
A method for treating a viral infection in a subject comprising administering to the subject an effective amount of a bivalent siRNA chimera to inhibit expression genes of the virus infecting the subject, wherein the bivalent siRNA chimera comprises first and second ends, wherein the first and second ends comprise an aptamer that specifically binds a cell surface viral protein expressed by virally infected cells; and an siRNA construct between the first and second ends, wherein the siRNA construct is processed by cellular RNAi machinery of the cells to produce at least two different siRNAs that specifically inhibit expression of two or more different genes of the infecting virus.
Across the independent claim set, the core inventive concept is a bivalent aptamer-siRNA chimera with aptamer-targeted first and second ends and an siRNA construct processed by cellular RNAi machinery to generate at least two different siRNAs that inhibit two or more genes, applied to cancer cell apoptosis, reduction of tumor burden, reduction of tumor-associated angiogenesis, and treatment of viral infection.
Stated Advantages
Induce or promote apoptosis of cancer cells.
Reduce tumor burden.
Reduce tumor associated angiogenesis.
Treat a viral infection by inhibiting expression genes of the infecting virus.
Documented Applications
Killing cancer cells in a subject by administering a bivalent siRNA chimera.
Reducing tumor burden in a subject by administering a bivalent siRNA chimera.
Reducing tumor associated angiogenesis in a subject by administering a bivalent siRNA chimera.
Treating a viral infection in a subject by administering a bivalent siRNA chimera.
Interested in licensing this patent?