Double stranded rna compounds to rhoa and use thereof
AssigneeQuark Pharmaceuticals, Inc.
InventorsSharon Avkin-Nachum, Elena Feinstein, Hagar Kalinski, Igor Mett
Life of this patent
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Abstract
The present invention relates to compounds, pharmaceutical compositions comprising same, methods of use thereof and kits for the down-regulation of RhoA gene. The compounds, compositions, methods and kits are useful in the treatment of subjects suffering from diseases or conditions and or symptoms associated with diseases or conditions in which RhoA expression has adverse consequences and for conferring neuroprotection.
Claims85
A double stranded nucleic acid molecule comprising a sense strand and an antisense strand wherein the sense and antisense strands are selected from an oligonucleotide described as RHOA_48 (SEQ ID NOS:
- 79 and 113), RHOA_48u (SEQ ID NOS:
- 80 and 114), RHOA_50 (SEQ ID NOS:
- 82 and 116) or RHOA_58 (SEQ ID NOS:
- 143 and 157).
A double stranded nucleic acid molecule wherein the antisense strand (SEQ ID NO:114) includes (5′>3′) one or more 2′OMe sugar modified ribonucleotides, a mirror nucleotide or a 2′-5′ linked ribonucleotide in one or more of positions 5, 6, 7 or 8 (5′>3′), and a 3′ terminal nucleotide or non-nucleotide overhang;
- and the sense strand (SEQ ID NO:80) includes (5′>3′) 4 or 5 consecutive 2′-5′ linked nucleotides at the 3′ terminal or penultimate positions, a nucleotide or non-nucleotide moiety covalently attached at the 3′ terminus and a cap moiety covalently attached at the 5′ terminus.
A double stranded nucleic acid molecule of claim 24 described as RHOA_50_S1796.
A double stranded nucleic acid molecule having the structure (A1):
- (A1)
- 5′ (N)x - Z 3′
- (antisense strand)
- 3′ Z′-(N′)y -z″ 5′
- (sense strand)
- wherein each N and N′ is a ribonucleotide which may be unmodified or modified, or an unconventional moiety;
- wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;
- wherein each of Z and Z′ is independently present or absent, but if present independently comprises 1-5 consecutive nucleotides, 1-5 consecutive non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present;
- wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of (N′)y;
- each of x and y is independently an integer from 18 to 40;
- wherein the sequence of (N′)y is complementary to the sequence of (N)x;
- and
- wherein (N)x comprises an antisense sequence set forth in Table III.
A double stranded nucleic acid molecule having a structure (A2) set forth below:
- (A2)
- 5′ N1-(N)x - Z 3′
- (antisense strand)
- 3′ Z′-N2-(N′)y-z″ 5′
- (sense strand)
- wherein each N1, N2, N and N′ is independently an unmodified or modified nucleotide, or an unconventional moiety;
- wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the adjacent N or N′ by a covalent bond;
- wherein each of x and y is independently an integer between 17 and 39;
- wherein N2 is covalently bound to (N′)y;
- wherein N1 is covalently bound to (N)x and is mismatched to the target mRNA (SEQ ID NO:1) or is a complementary DNA moiety to the target mRNA;
- wherein N1 is a moiety selected from the group consisting of natural or modified:
- uridine, deoxyribouridine, ribothymidine, deoxyribothymidine, adenosine or deoxyadenosine, an abasic ribose moiety and an abasic deoxyribose moiety;
- wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of N2-(N′)y;
- wherein each of Z and Z′ is independently present or absent, but if present is independently 1-5 consecutive nucleotides, 1-5 consecutive non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present;
- and
- wherein the sequence of (N′)y is complementary to the sequence of (N)x;
- and
- wherein the sequence of (N)x comprises an antisense sequence set forth in Table I.
A composition comprising a double stranded molecule of any of the preceding claims packaged for use by a patient.
The composition of 50, wherein the composition includes a label or package insert that provides information about how said double stranded molecule of any of the preceding claims may be used.
A method of reducing the expression of RhoA in a cell, comprising introducing into a cell a double stranded molecule of any of the preceding claims in an amount sufficient to reduce expression of RhoA.
Dependencies are inferred from the claim text.