Compositions and methods for inhibiting expression of RRM2 genes
Inventors
Boylan, John Frederick • Bramlage, Birgit • Hossbach, Markus • Reidhaar-Olson, John
Assignees
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Publication Number
US-11920134-B2
Publication Date
2024-03-05
Expiration Date
Abstract
The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a RRM2 gene. The invention also relates to a pharmaceutical composition comprising the dsRNA or nucleic acid molecules or vectors encoding the same together with a pharmaceutically acceptable carrier; methods for treating diseases caused by the expression of a RRM2 gene using said pharmaceutical composition; and methods for inhibiting the expression of RRM2 in a cell.
Core Innovation
The invention relates to a double-stranded ribonucleic acid molecule for inhibiting the expression of a ribonucleotide reductase M2 (RRM2) gene. The molecule comprises a sense strand and an antisense strand, where the antisense strand and the sense strand are each less than about 30 nucleotides in length, and the sense strand is at least substantially complementary to the antisense strand. The antisense strand comprises the nucleotide sequence of any of SEQ ID NO: 259, 279, 307, 309, 314, 333, 344, 363 or 395.
The double-stranded ribonucleic acid molecule includes at least one modified nucleotide in the sense strand and/or the antisense strand. In the described refinements, the sense and antisense strands can each be 19-24 nucleotides in length, and the sense strand can comprise nucleotide sequences corresponding to particular SEQ ID NOs. The antisense strand can include specific modified nucleotides, such as 2′-O-methyl modified nucleotides, 2′-deoxy-2′-fluoro modified nucleotides, and nucleotides with 5′-phosphorothioate groups.
Additional described features include a 3′ overhang that is 1 to 5 nucleotides long for the sense and/or antisense strand. The invention also encompasses embodiments in which the double-stranded ribonucleic acid molecule is conjugated to a ligand, and embodiments formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier, and includes vectors encoding the dsRNA strands and cells comprising such vectors.
Claims Coverage
The claim content covers four inventive features centered on a dsRNA design for inhibiting RRM2 expression, including short strand length, specified antisense sequences, substantial complementarity, and modified nucleotides, with dependent refinements for strand-length constraints, specific nucleotide modification types, a 3′ overhang, ligand conjugation, and pharmaceutical formulation.
Double-stranded ribonucleic acid inhibiting RRM2 expression
A double-stranded ribonucleic acid molecule for inhibiting the expression of a ribonucleotide reductase M2 (RRM2) gene.
Short sense and antisense strands with complementary relationship
The double-stranded ribonucleic acid molecule comprises a sense strand and an antisense strand, wherein the antisense strand and the sense strand are each less than about 30 nucleotides in length, and wherein the sense strand is at least substantially complementary to the antisense strand.
Antisense strand with enumerated SEQ ID NO nucleotide sequence
The antisense strand comprises the nucleotide sequence of any of SEQ ID NO: 259, 279, 307, 309, 314, 333, 344, 363 or 395.
Modified nucleotides in sense and/or antisense strand
The sense strand and/or the antisense strand comprises at least one modified nucleotide.
Overall claim coverage centers on dsRNA that inhibits RRM2 expression via short complementary sense and antisense strands, where the antisense strand uses enumerated SEQ ID NO sequences and at least one modified nucleotide is incorporated in the sense and/or antisense strand.
Stated Advantages
Inhibiting expression of a ribonucleotide reductase M2 (RRM2) gene.
Reduced IFN-α and TNF-α induction is described in the provided content.
Documented Applications
Inhibiting RRM2 expression for tumor and inflammatory indications, including hepatocellular carcinoma (HCC), leukemia, and solid tumors.
Examples of specific indications listed include AML, bladder cancer, prostate cancer, NSCLC, breast cancer, and colorectal cancer.
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