Sirna compounds comprising terminal substitutions
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Publication Number
US-8796239-B2
Publication Date
2014-08-05
Expiration Date
Abstract
The invention relates to modified siRNA compounds which down-regulate target gene expression, to pharmaceutical compositions comprising such compounds and to methods of treating and/or preventing the incidence or severity of various diseases or conditions associated with the genes and/or symptoms associated with such diseases or conditions.
Core Innovation
The invention relates to a double-stranded nucleic acid having structure (A) with an antisense strand and a sense strand. The sequence of N2-(N)y is fully complementary to the sequence of N1-(N)x, and the sequence of (N)x has complementarity to a consecutive sequence in a target RNA.
Each consecutive N or N in oligonucleotide segments (N)x and (N)y is joined by a covalent bond. N1 is covalently bound to (N)x and is not complementary to the corresponding nucleotide in the target RNA or is an unconventional moiety complementary to the target RNA. N1 is selected from specified groups depending on whether the corresponding target RNA nucleotide is adenosine, cytidine, guanosine, or uridine.
The structure (A) includes optional end moieties, with z/z3 possibly present or absent as a capping moiety covalently attached at the 5 terminus of N2-(N)y. Each of Z and Z is independently present or absent, and if present is covalently attached at the 3 terminus of the strand in which it is present, with the option that terminal groups include 1-5 consecutive nucleotides and/or non-nucleotide moieties. The invention covers the double-stranded nucleic acid and pharmaceutically acceptable salts of the double-stranded nucleic acid.
Claims Coverage
The independent claims cover a double-stranded nucleic acid defined by structure (A), full antisense/sense complementarity, complementarity of (N)x to a consecutive target RNA sequence, and a covalently bound N1 position selected based on the corresponding nucleotide in the target RNA. Across the independent claims, there are 5 inventive features.
Structure (A) antisense and sense strand architecture
A double-stranded nucleic acid having an antisense strand and a sense strand, wherein each of N2, N, and N is an unmodified ribonucleotide, a modified ribonucleotide, or an unconventional moiety, and 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.
Full complementarity and target RNA complementarity
The sequence of N2-(N)y is fully complementary to the sequence of N1-(N)x, and the sequence of (N)x has complementarity to a consecutive sequence in a target RNA.
Covalently bound N1 non-complementary or unconventional moiety complementary
N1 is covalently bound to (N)x and is not complementary to the corresponding nucleotide in the target RNA or is an unconventional moiety complementary to the target RNA; N1 is selected from specified groups depending on whether the corresponding nucleotide in the target RNA is adenosine, cytidine, guanosine, or uridine.
Optional 5 capping and optional 3 terminal groups Z/Z
z/z3 may be present or absent, but if present is a capping moiety covalently attached at the 5 terminus of N2-(N)y; 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 covalently attached at the 3 terminus of the strand in which it is present.
Pharmaceutically acceptable salt coverage
The invention covers a pharmaceutically acceptable salt of the double-stranded nucleic acid.
Overall claim coverage is directed to a structured double-stranded nucleic acid with defined antisense/sense architecture and full complementarity, combined with a covalently bound N1 position whose identity and complementary behavior are selected based on the corresponding nucleotide in the target RNA, along with optional 5 capping, optional 3 terminal groups, and pharmaceutically acceptable salts.
Stated Advantages
Enhanced knockdown/activity versus fully complementary unmodified controls.
Reduced off-target activity compared to controls, while retaining guide-site/on-target activity.
Documented Applications
In vitro testing/application context for siRNA duplexes targeting genes including TLR2, CAPNS1, and RHOA using qPCR and psiCHECK reporter assays.
Pharmaceutical use areas and disease or condition categories enumerated in dependent coverage include hearing loss; acute renal failure (ARF); delayed graft function (DGF) after kidney transplantation; glaucoma; ocular ischemic conditions; non-arteric ischemic optic neuropathy (NAION); anterior ischemic optic neuropathy; age-related macular degeneration (AMD); ischemic optic neuropathy (ION); dry eye syndrome; acute respiratory distress syndrome (ARDS); other acute lung and respiratory injuries; chronic obstructive pulmonary disease (COPD); primary graft failure; ischemia-reperfusion injury; reperfusion injury; reperfusion edema; allograft dysfunction; pulmonary reimplantation response and/or primary graft dysfunction (PGD) after organ transplantation; organ transplantation including lung, liver, heart, pancreas, kidney transplantation; nephro- and neurotoxicity; spinal cord injury; brain injury; neurodegenerative disease or condition; pressure sores; oral mucositis; fibrotic disorders; and cancer.
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