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US 12,655,432 B2Granted
Oligonucleotides for SOD1 modulation
AssigneeUniversity of Massachusetts
InventorsAnastasia Khvorova, James W. Gilbert, Chantal Ferguson, Robert Brown, Alexandra Weiss
Life of this patent
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Abstract
This disclosure relates to novel SOD1 targeting sequences. Novel SOD1 targeting oligonucleotides for the treatment of SOD1-related familial amyotrophic lateral sclerosis (ALS).
Claims18
A double stranded RNA (dsRNA) molecule comprising an antisense strand and a sense strand, each strand with a 5′ end and a 3′ end, wherein:
- (1) the antisense strand comprises a sequence complementary to a superoxide dismutase 1 (SOD1) nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides;
- (3) the nucleotides at positions 2 and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides;
- and
- (7) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 70% 2′-O-methyl modifications;
- (3) the nucleotide at position 14 from the 5′ end of the antisense strand is not a 2′-methoxy-ribonucleotide;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 70% 2′-O-methyl modifications;
- and
- (7) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 75% 2′-O-methyl modifications;
- (3) the nucleotides at positions 2, 6, 14, and 16 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 65% 2′-O-methyl modifications;
- (7) the nucleotides at positions 7, 9, 10, and 11 from the 3′ end of the sense strand are not 2′-methoxy-ribonucleotides;
- and
- (8) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 75% 2′-O-methyl modifications;
- (3) the nucleotides at positions 2 and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 75% 2′-O-methyl modifications;
- (7) the nucleotides at positions 7, 10, and 11 from the 3′ end of the sense strand are not 2′-methoxy-ribonucleotides;
- and
- (8) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- or
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 50% 2′-O-methyl modifications;
- (3) the nucleotides at positions 2 and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 65% 2′-O-methyl modifications;
- (7) the nucleotides at positions 3, 7, 9, 11, and 13 from the 3′ end of the sense strand are not 2′-methoxy-ribonucleotides;
- and
- (8) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages.
46 more elements
A dsRNA comprising an antisense strand and a sense strand, each strand with a 5′ end and a 3′ end, wherein:
- (1) the antisense strand comprises a sequence complementary to a superoxide dismutase 1 (SOD1) nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises the chemical modification pattern of:
- (mX)#(fX)#(mX)(fX)(fX)(fX)(mX)(fX)(mX)(fX)(mX)(fX)(mX)(fX)#(mX)#(fX)#(mX)#(mX)#(mX)#(fX)#(mX);
- (3) a portion of the antisense strand is complementary to a portion of the sense strand;
- and
- (4) the sense strand comprises the chemical modification pattern of:
- (mX)#(mX)#(mX)(fX)(mX)(fX)(mX)(fX)(mX)(fX)(mX)(mX)(mX)(fX)#(mX)#(mX), wherein “m” corresponds to a 2′-O-methyl modification;
- “f” corresponds to a 2′-fluoro modification;
- “#” corresponds to a phosphorothioate internucleotide linkage;
- and “X” corresponds to any nucleotide of A, U, G, or C;
- or
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises the chemical modification pattern of:
- (mX)#(fX)#(mX)(mX)(mX)(fX)(mX)(mX)(mX)(mX)(mX)(mX)(mX)(fX)#(mX)#(fX)#(mX) #(mX)#(mX)#(fX)#(mX);
- (3) a portion of the antisense strand is complementary to a portion of the sense strand;
- and
- (4) the sense strand comprises the chemical modification pattern of:
- (mX)#(mX)#(mX)(mX)(mX)(fX)(fX)(fX)(mX)(fX)(mX)(mX)(mX)(mX)#(mX)#(mX), wherein “m” corresponds to a 2′-O-methyl modification;
- “f” corresponds to a 2′-fluoro modification;
- “#” corresponds to a phosphorothioate antinucleotide linkage;
- and “X” corresponds to any nucleotide of A, U, G, or C.
20 more elements
A branched RNA compound comprising:
- two or more RNA molecules comprising 15 to 35 nucleotides in length, wherein at least one of the two or more RNA molecules comprises a double stranded RNA (dsRNA), wherein two of the two or more RNA molecules are connected to one another by one or more moieties independently selected from a linker, a spacer, and a branching point;
- and
- a sequence complementary to a superoxide dismutase 1 (SOD1) mRNA,
- wherein the dsRNA comprises an antisense strand and a sense strand, each strand with a 5′ end and a 3′ end, wherein:
- A:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides;
- (3) the nucleotides at positions 2 and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides;
- and
- (7) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- B:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 70% 2′-O-methyl modifications;
- (3) the nucleotide at position 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 70% 2′-O-methyl modifications;
- and
- (7) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- C:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 75% 2′-O-methyl modifications;
- (3) the nucleotides at positions 4, 5, 6, and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises 100% 2′-O-methyl modifications;
- and
- (7) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- D:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 75% 2′-O-methyl modifications;
- (3) the nucleotides at positions 2, 6, 14, and 16 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 65% 2′-O-methyl modifications;
- (7) the nucleotides at positions 7, 9, 10, and 11 from the 3′ end of the sense strand are not 2′-methoxy-ribonucleotides;
- and
- (8) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- E:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 75% 2′-O-methyl modifications;
- (3) the nucleotides at positions 2 and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 75% 2′-O-methyl modifications;
- (7) the nucleotides at positions 7, 10, and 11 from the 3′ end of the sense strand are not 2′-methoxy-ribonucleotides;
- and
- (8) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages;
- or
- F:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises at least 50% 2′-O-methyl modifications;
- (3) the nucleotides at positions 2 and 14 from the 5′ end of the antisense strand are not 2′-methoxy-ribonucleotides;
- (4) the nucleotides at positions 1-2 to 1-7 from the 3′ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages;
- (5) a portion of the antisense strand is complementary to a portion of the sense strand;
- (6) the sense strand comprises at least 65% 2′-O-methyl modifications;
- (7) the nucleotides at positions 3, 7, 9, 11, and 13 from the 3′ end of the sense strand are not 2′-methoxy-ribonucleotides;
- and
- (8) the nucleotides at positions 1-2 from the 5′ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages.
65 more elements
A branched RNA compound comprising:
- two or more double stranded RNA (dsRNA), each dsRNA comprising an antisense strand and a sense strand, each strand with a 5′ end, a 3′ end, and a length of 15 to 35 nucleotides;
- and
- a sequence complementary to a superoxide dismutase 1 (SOD1) mRNA, wherein:
- (1) the antisense strand comprises a sequence complementary to a SOD1 nucleic acid sequence of any one of SEQ ID NOs:
- 1-11;
- (2) the antisense strand comprises the chemical modification pattern of:
- (mX)#(fX)#(mX)(fX)(fX)(fX)(mX)(fX)(mX)(fX)(mX)(fX)(mX)(fX)#(mX)#(fX)#(mX)#(mX) #(mX)#(fX)#(mX);
- (3) a portion of the antisense strand is complementary to a portion of the sense strand;
- and
- (4) the sense strand comprises the chemical modification pattern of:
- (mX)#(mX)#(mX)(fX)(mX)(fX)(mX)(fX)(mX)(fX)(mX)(mX)(mX)(fX)#(mX)#(mX), wherein “m” corresponds to a 2′-O-methyl modification;
- “f” corresponds to a 2′-fluoro modification;
- “#” corresponds to a phosphorothioate internucleotide linkage;
- and “X” corresponds to any nucleotide of A, U, G, or C,
- wherein the two or more dsRNA are connected to one another by one or more moieties independently selected from a linker, a spacer and a branching point.
12 more elements
Dependencies are inferred from the claim text.