Bi-functional shRNA targeting Stathmin 1 and uses thereof
Inventors
Rao, Donald • Nemunaitis, John J. • Senzer, Neil
Assignees
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Publication Number
US-8906874-B2
Publication Date
2014-12-09
Expiration Date
Abstract
The present invention includes bifunctional shRNAs capable of reducing an expression of a Stathmin 1 gene; wherein at least one target site sequence of the bifunctional RNA molecule is located within the Stathmin 1 gene, wherein the bifunctional RNA molecule is capable of activating a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of Stathmin 1.
Core Innovation
The invention relates to using an expression vector that expresses one or more shRNAs capable of inhibiting Stathmin 1 in target cells via RNA interference. The shRNAs are bifunctional RNA molecules that activate both a cleavage-dependent and a cleavage-independent RNA-induced silencing complex, thereby reducing the expression level of Stathmin 1.
The disclosed design specifies that the bifunctional shRNAs target Stathmin 1 in ways that involve activation of the cleavage-dependent and cleavage-independent RISC pathways. In the described constructs, the inhibition is achieved through a bi-shRNA approach in which mature shRNA is associated with cleavage-dependent and cleavage-independent components.
The invention further describes delivering the expression vector in therapeutic agent carrier complex formats, including compacted DNA nanoparticles and bilamellar invaginated vesicles. The described delivery concepts include use of specific carrier formulations and optional receptor-targeting or masking features for in vivo administration.
Claims Coverage
The independent claims are directed to methods for suppressing tumor cell growth in a subject using an expression-vector therapeutic agent carrier complex with bifunctional shRNAs that inhibit Stathmin 1 via RNA interference. Across the independent claims, three core inventive elements recur: bifunctional shRNAs activating cleavage-dependent and cleavage-independent RISC, Stathmin 1 targeting through RNA interference, and a resulting functional outcome.
Bifunctional shRNA-mediated Stathmin 1 inhibition for tumor growth suppression
The one or more shRNAs comprise a bifunctional RNA molecule that activates a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of the target gene Stathmin 1.
Expression-vector delivery of shRNAs to inhibit Stathmin 1 via RNA interference
Administering an expression vector in a therapeutic agent carrier complex to the human subject in an amount sufficient to suppress the tumor cell growth, wherein the expression vector expresses one or more shRNAs capable of inhibiting an expression of a target gene that is Stathmin 1 in the one or more target cells via RNA interference.
Functional outcome of Stathmin 1 inhibition in tumor cells
Wherein the inhibition results in an apoptosis, an arrested proliferation, or a reduced invasiveness of the tumor cells.
Stathmin-1 target-site region targeting by bifunctional shRNAs
The shRNAs target at least one of the 5′-UTR, the coding region, or the 3′-UTR of the Stathmin-1, or overlapping portions thereof, wherein the one or more shRNAs comprise a bifunctional RNA molecule that activates a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of the target gene.
Therapeutic composition delivering expression-vector shRNAs in a carrier complex
Administering a composition comprising an expression vector that expresses one or more shRNAs capable of inhibiting an expression of a target gene that is Stathmin 1 in the one or more target cells via RNA interference, and the shRNAs target at least one of the 5′-UTR, the coding region, or the 3′-UTR of Stathmin-1, or overlapping portions thereof in a therapeutic agent carrier complex to the subject in an amount sufficient to suppress the tumor cell growth.
Both independent claims cover methods that suppress tumor cell growth by delivering an expression vector expressing bifunctional shRNAs that activate both cleavage-dependent and cleavage-independent RNA-induced silencing complex activity to reduce Stathmin 1 expression, with the inhibition producing apoptosis, arrested proliferation, or reduced invasiveness; one claim further specifies target-site selection within the 5′-UTR, coding region, or 3′-UTR (or overlapping portions).
Stated Advantages
Suppresses tumor cell growth in a human subject.
Inhibits Stathmin 1 expression via RNA interference by activating cleavage-dependent and cleavage-independent RISC.
Results in apoptosis, arrested proliferation, or reduced invasiveness of tumor cells.
Documented Applications
Methods of suppressing a tumor cell growth in a human subject by administering an expression vector expressing Stathmin 1-targeting bifunctional shRNAs in a therapeutic agent carrier complex.
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