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US 2015/0307885 A1Published application
Multiple targeted rnai for the treatment of cancers
AssigneesStrike Bio, Inc., Baylor College of Medicine
InventorsDonald Rao, John Nemunaitis, Bert W. O'Malley, David Lonard
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Abstract
The present invention includes compositions and methods for making and using a RNAi capable of reducing expression of two or more genes, comprising: a first RNAi molecule that reduces the expression of a first target gene; a second RNAi molecule that reduces the expression of the first or a second target gene; and optionally a third RNAi molecule that reduces the expression of the first, the second, or a third target gene, wherein the RNAi molecules reduce the expression level of, e.g., mutated KRAS, SRC-3, EGFR, PIK3, NCOA3, or ERalpha1, and can be, e.g., miRNAs, shRNAs, or bifunctional shRNAs.
Claims43
A bifunctional shRNA composition capable of reducing expression of three or more genes, comprising:
- a first bifunctional RNA molecule that reduces the expression of a first gene target;
- a second bifunctional RNA molecule that reduces the expression of a second gene target;
- and
- a third bifunctional RNA molecule that reduces the expression of a third gene target, wherein each of the bifunctional RNA molecules are capable of activating a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of the first, second and third gene target.
1 more element
An expression vector comprising:
- a promoter;
- and
- a nucleic acid insert operably linked to the promoter, wherein the insert comprises:
- a first bifunctional RNA molecule that reduces the expression of s first target gene;
- a second bifunctional RNA molecule that reduces the expression of a second target gene;
- and
- a third bifunctional RNA molecule that reduces the expression of a third target 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 the first, second and third target genes, wherein the one or more shRNA 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 first, second and third target genes.
4 more elements
A therapeutic delivery system comprising:
- a therapeutic agent carrier;
- and
- an expression vector comprising a promoter and a nucleic acid insert operably linked to the promoter, the nucleic acid insert encoding:
- a first bifunctional RNA molecule that reduces the expression of a first gene target;
- a second bifunctional RNA molecule that reduces the expression of a second gene target;
- and
- a third bifunctional RNA molecule that reduces the expression of a third gene target, wherein each of the bifunctional RNA molecules are capable of activating a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of the first, second and third gene target.
4 more elements
A method to deliver one or more shRNAs to a target tissue expressing a KRAS, SRC-3 and EGFR gene comprising the steps of:
- preparing an expression vector comprising a promoter and a nucleic acid insert operably linked to the promoter that encodes the one or more shRNA, wherein the one or more shRNA comprise a nucleic acid insert operably linked to the promoter, wherein the insert comprises:
- a first bifunctional RNA molecule that reduces the expression of a first gene target;
- a second bifunctional RNA molecule that reduces the expression of a second gene target;
- and
- a third bifunctional RNA molecule that reduces the expression of a third gene target, wherein each of the bifunctional RNA molecules are capable of activating a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of the first, second and third gene target;
- combining the expression vector with a therapeutic agent carrier, wherein the therapeutic agent carrier comprises a liposome;
- and
- administering a therapeutically effective amount of the expression vector and therapeutic agent carrier complex to a patient in need thereof.
5 more elements
A method of suppressing a tumor cell growth in a human subject comprising the steps of:
- identifying the human subject in need for suppression of the tumor cell growth;
- and
- 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 comprises a nucleic acid insert operably linked to the promoter, wherein the insert comprises:
- a first bifunctional RNA molecule that reduces the expression of a mutated KRAS gene;
- a second bifunctional RNA molecule that reduces the expression of a SRC-3 gene;
- and
- a third bifunctional RNA molecule that reduces the expression of a Epidermal Growth Factor Receptor (EGFR) 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 mutated KRAS, SRC-3 and EGFR, and wherein the inhibition results in an apoptosis, an arrested proliferation, or a reduced invasiveness of the tumor cells.
4 more elements
A method of evaluating a candidate drug believed to be useful in treating a cancer, the method comprising:
- (a) measuring one or more of the following:
- the level of expression of at least a wild-type KRAS and one or more mutated KRAS, and two or more target genes in the cancer cells or tissues;
- the level of expression of a candidate gene or a group of candidate genes in an cellular environment with the lowered expression of one or more mutated KRAS, genes and the two or more target genes in the cancer cells or tissues;
- the effect of a candidate drug on the phenotype of such cells comprised of lowered expression of one or more mutated KRAS genes and the two or more target genes in the cancer cells or tissues;
- (b) administering a candidate drug to a first subset of said cancer cells or tissues, and a placebo to a second subset of said cancer cells or tissues;
- (c) repeating step (a) after the administration of the candidate drug or the placebo;
- and
- (d) determining if the candidate drug is effective in producing determined phenotype in an cellular environment with reduced expression of mutated KRAS and the two or more target genes as compared to normal KRAS expressing cellular environment that is statistically significant as compared to any reduction occurring in the second subset of lung cancer cells or tissues, wherein a statistically significant reduction indicates that the candidate drug is useful in treating cancer.
5 more elements
A method of suppressing the growth of tumor cells in a human subject comprising the steps of:
- obtaining a tumor cell sample from the human subject;
- identifying one or more target gene or genes in the human subject in need for suppression to prevent tumor cell growth;
- constructing a expression vector that comprises an insert that expresses two or more RNAi nucleic acid segments that specifically target the gene or genes identified in the tumor cell sample;
- wherein the insert comprises:
- a first and a second RNAi nucleic acid that reduces the expression of the same or different target gene or genes identified in the tumor cell;
- administering the expression vector in a therapeutic agent carrier complex to the human subject in an amount sufficient to express the two or more RNAi nucleic acid segments;
- and
- determining whether the gene or genes have been knocked-down by the expression vector in the target tumor cells, wherein the inhibition results in an apoptosis, an arrested proliferation, or a reduced invasiveness of the tumor cells.
5 more elements
Dependencies are inferred from the claim text.