US2024018496A1PendingUtilityA1

Compositions and Methods for Kallikrein (KLKB1) Gene Editing

77
Assignee: INTELLIA THERAPEUTICS INCPriority: Feb 7, 2020Filed: Jul 31, 2023Published: Jan 18, 2024
Est. expiryFeb 7, 2040(~13.6 yrs left)· nominal 20-yr term from priority
Inventors:Shobu OdateJessica Lynn Seitzer
C12N 9/22A61P 43/00C12N 15/102C12N 2310/20C12N 2310/32C12N 15/113C12N 2310/315C12N 2310/321A61K 31/712A61K 31/7125A61K 48/0066C12N 2310/322
77
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Claims

Abstract

Compositions and methods for editing, e.g., introducing double-stranded breaks, within the KLKB1 gene are provided. Compositions and methods for treating subjects having hereditary angioedema (HAE), are provided.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A composition comprising (i) a single guide RNA (sgRNA) comprising in 5′ to 3′ order: 1) a guide sequence of SEQ ID NO: 15, and 2) a sequence of SEQ ID NO: 171. 
     
     
         2 . A method of treating hereditary angioedema (HAE) comprising administering to a human subject in need thereof a therapeutically effective amount of i) a single guide RNA (sgRNA) comprising in 5′ to 3′ order: 1) a guide sequence of SEQ ID NO: 15, and 2) a sequence of SEQ ID NO: 171. 
     
     
         3 . The composition of  claim 1 , further comprising a Cas9 or a nucleic acid encoding a Cas9. 
     
     
         4 . The composition of  claim 3 , wherein the Cas9 is encoded by a nucleic acid comprising SEQ ID NO: 511. 
     
     
         5 . The composition of  claim 1 , wherein the sgRNA comprises at least one modification. 
     
     
         6 . The composition of  claim 5 , wherein the modification comprises (a) a 5′ end modification, (b) a 3′ end modification, and/or (c) a modification in a hairpin region. 
     
     
         7 . The composition of  claim 5 , wherein the modification comprises (a) a 2′-O-methyl (2′-O-Me) modified nucleotide, (b) a phosphorothioate (PS) bond between nucleotides, and/or (c) a 2′-fluor (2′-F) modified nucleotide. 
     
     
         8 . The composition of  claim 5 , wherein the nucleotide sequence of SEQ ID NO: 171 is modified according to the pattern of nucleotide sequence of SEQ ID NO: 405. 
     
     
         9 . The composition of  claim 1 , wherein the sgRNA comprises a modification pattern of SEQ ID NO: 300. 
     
     
         10 . The composition of  claim 1 , comprising the following modified sequence: mG*mG*mA*UUGCGUAUGGGACACAAGUUUUAGAmGmCmUmAmGmAmAmAmU mAmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAm AmAmGmUmGmGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU*mU*mU*mU, wherein “mA,” “mC,” “mU,” or “mG” denote a nucleotide that has been modified with 2′-O-Me, and a * denotes a phosphorothioate bond. 
     
     
         11 . The composition of  claim 10 , further comprising a Cas9 or a nucleic acid encoding a Cas9. 
     
     
         12 . The composition of  claim 11 , wherein the Cas9 is encoded by a nucleic acid comprising SEQ ID NO: 511. 
     
     
         13 . The composition of  claim 1 , wherein the sgRNA is associated with a lipid nanoparticle (LNP). 
     
     
         14 . The composition of  claim 10 , wherein the sgRNA is associated with a lipid nanoparticle (LNP). 
     
     
         15 . The composition of  claim 12 , wherein the sgRNA is associated with a lipid nanoparticle (LNP). 
     
     
         16 . The composition of  claim 13 , wherein the LNP comprises an ionizable lipid, wherein the ionizable lipid is (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate. 
     
     
         17 . A pharmaceutical composition comprising the sgRNA of  claim 1  and further comprising a pharmaceutical excipient or carrier. 
     
     
         18 . The method of  claim 2 , further comprising administering a Cas9 or a nucleic acid encoding a Cas9. 
     
     
         19 . The method of  claim 18 , wherein the Cas9 is encoded by a nucleic acid comprising SEQ ID NO: 511. 
     
     
         20 . The method of  claim 2 , wherein the sgRNA comprises at least one modification. 
     
     
         21 . The method of  claim 20 , wherein the modification comprises (a) a 5′ end modification, (b) a 3′ end modification, and/or (c) a modification in a hairpin region. 
     
     
         22 . The method of  claim 20 , wherein the modification comprises (a) a 2′-O-methyl (2′-O-Me) modified nucleotide, (b) a phosphorothioate (PS) bond between nucleotides, and/or (c) a 2′-fluor (2′-F) modified nucleotide. 
     
     
         23 . The method of  claim 20 , wherein the nucleotide sequence of SEQ ID NO: 171 is modified according to the pattern of nucleotide sequence of SEQ ID NO: 405. 
     
     
         24 . The method of  claim 2 , wherein the sgRNA comprises a modification pattern of SEQ ID NO: 300. 
     
     
         25 . The method of  claim 2 , comprising administering the following modified sequence: mG*mG*mA*UUGCGUAUGGGACACAAGUUUUAGAmGmCmUmAmGmAmAmAmU mAmGmCAAGUUAAAAUAAGGCUAGUCCGUUAUCAmAmCmUmUmGmAmAmAm AmAmGmUmGmGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU*mU*mU*mU, wherein “mA,” “mC,” “mU,” or “mG” denote a nucleotide that has been modified with 2′-O-Me, and a * denotes a phosphorothioate bond. 
     
     
         26 . The method of  claim 25 , further comprising administering a Cas9 or a nucleic acid encoding a Cas9. 
     
     
         27 . The method of  claim 26 , wherein the Cas9 is encoded by a nucleic acid comprising SEQ ID NO: 511. 
     
     
         28 . The method of  claim 2 , wherein the sgRNA is associated with a lipid nanoparticle (LNP). 
     
     
         29 . The method of  claim 28 , wherein the LNP comprises an ionizable lipid, wherein the ionizable lipid is (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate, also called 3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate. 
     
     
         30 . The method of  claim 2 , wherein treating the subject comprises reducing the frequency and/or severity of HAE attacks.

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