IP Library › Granted Patent US 12,655,432
Granted Patent B2
US 12,655,432 · App. 17/982,993 · Granted Jun 16, 2026

Oligonucleotides for SOD1 modulation

Inventors: Anastasia Khvorova (Westborough, MA); James W. Gilbert (Worcester, MA); Chantal Ferguson (Worcester, MA); Robert Brown (Needham, MA); Alexandra Weiss (Bolton, MA)
Assignee: UNIVERSITY OF MASSACHUSETTS
C12N15/1137A61P25/28C12N2310/14C12N2310/315C12N2310/321C12N2310/322C12N2320/32
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Quick Facts
Patent No.
US 12,655,432
App. No.
17/982,993
Granted
Jun 16, 2026
Kind
B2
Abstract

This disclosure relates to novel SOD1 targeting sequences. Novel SOD1 targeting oligonucleotides for the treatment of SOD1-related familial amyotrophic lateral sclerosis (ALS).

Claims (147)

1 . 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.

2 . The dsRNA molecule of claim 1 , wherein the antisense strand comprises 15 nucleotides to 25 nucleotides in length.

3 . The dsRNA molecule of claim 1 , wherein:

the dsRNA molecule further comprises at least one modified internucleotide linkage of Formula I:

wherein:

B is a base pairing moiety;

W is selected from the group consisting of O, OCH 2 , OCH, CH 2 , and CH;

X is selected from the group consisting of halo, hydroxy, and C 1-6 alkoxy;

Y is selected from the group consisting of O − , OH, OR, NH, NH 2 , S, and SH;

Z is selected from the group consisting of O and CH 2 ;

R is a protecting group; and

is an optional double bond.

4 . The dsRNA molecule of claim 1 , further comprising a functional moiety linked to the 5′ end and/or the 3′ end of the antisense strand or the sense strand.

5 . The dsRNA molecule of claim 1 , wherein the antisense strand further comprises a 5′ phosphate, a 5′-alkyl phosphonate, a 5′ alkylene phosphonate, or a 5′ alkenyl phosphonate.

6 . The dsRNA molecule of claim 5 , wherein the 5′ alkenyl phosphonate is a 5′ vinyl phosphonate.

7 . A pharmaceutical composition for inhibiting the expression of the SOD1 gene in an organism, comprising the dsRNA molecule of claim 1 and a pharmaceutically acceptable carrier.

8 . The pharmaceutical composition of claim 7 , wherein the dsRNA molecule inhibits expression of the SOD1 gene by at least 50% or at least 80%.

9 . 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.

10 . 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.

11 . The branched RNA compound of claim 10 , wherein at least one of the two or more dsRNA molecules further comprises at least one modified internucleotide linkage of Formula I:

wherein:

B is a base pairing moiety;

W is selected from the group consisting of O, OCH 2 , OCH, CH 2 , and CH;

X is selected from the group consisting of halo, hydroxy, and C 1-6 alkoxy;

Y is selected from the group consisting of O, OH, OR, NH, NH 2 , S, and SH;

Z is selected from the group consisting of O and CH 2 ;

R is a protecting group; and

is an optional double bond.

12 . The branched RNA compound of claim 10 , wherein the antisense strand further comprises a 5′ phosphate, a 5′-alkyl phosphonate, a 5′ alkylene phosphonate, a 5′ alkenyl phosphonate, or a mixture thereof.

13 . The branched RNA compound of claim 12 , wherein the 5′ alkenyl phosphonate is a 5′ vinyl phosphonate.

14 . The branched RNA compound of claim 10 , wherein the linker comprises an ethylene glycol chain, an alkyl chain, a peptide, an RNA, a DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, or combinations thereof.

15 . A pharmaceutical composition for inhibiting the expression of the SOD1 gene in an organism, comprising the branched RNA compound of claim 10 , and a pharmaceutically acceptable carrier.

16 . 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.

17 . The branched RNA compound of claim 16 , wherein the antisense strand further comprises a 5′ phosphate, a 5′-alkyl phosphonate, a 5′ alkylene phosphonate, or a 5′ alkenyl phosphonate.

18 . The branched RNA compound of claim 17 , wherein the 5′ alkenyl phosphonate is a 5′ vinyl phosphonate.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 8, 2026
From: KHVOROVA, ANASTASIA; GILBERT, JAMES W.; FERGUSON, CHANTAL; BROWN, ROBERT
To: UNIVERSITY OF MASSACHUSETTS
Reel/Frame 074600/0933 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 8, 2026
From: WEISS, ALEXANDRA
To: UNIVERSITY OF MASSACHUSETTS
Reel/Frame 074601/0005 →
Continuity (2)
Provisional Application 63276854 · Nov 8, 2021
Related Publication 20230193281A1 · Jun 22, 2023
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