Compositions and methods for the targeting of pcsk9
AssigneeScribe Therapeutics Inc.
InventorsJason FERNANDES, Sean HIGGINS, Sarah DENNY, Ross WHITE, Emeric Jean Marius CHARLES, Addison WRIGHT, Benjamin DEMAREE, Manuel MOHR, Wenyuan ZHOU, Benjamin OAKES
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Abstract
Provided herein are gene repressor systems comprising fusion proteins, such as fusion proteins comprising a DNA binding domain such as a TALE, zinc finger or catalytically-dead CRISPR protein and guide nucleic acid (gRNA), which are useful in the repression of a proprotein convertase subtilisin/kexin Type 9 (PCSK9) gene. Also provided are methods of using such systems to repress transcription of PCSK9.
Claims28
A system comprising a repressor fusion protein and a guide ribonucleic acid (gRNA), wherein the repressor fusion protein comprises:
- (a) a catalytically-dead CRISPR protein;
- (b) a repressor domain (RD1);
- (c) a DNA methyltransferase (DNMT) 3A ATRX-DNMT3-DNMT3L domain (ADD);
- (d) a DNMT3A catalytic domain (DNMT3A);
- and
- (e) a DNMT3L domain (DNMT3L),
- wherein the gRNA comprises a targeting sequence complementary to a proprotein convertase subtilisin/kexin Type 9 (PCSK9) gene target nucleic acid sequence, and
- wherein the repressor fusion protein is capable of forming a ribonucleoprotein (RNP) with the gRNA.
(canceled)
A composition comprising
- (a) a first nucleic acid comprising a guide ribonucleic acid (gRNA) comprising a targeting sequence complementary to a proprotein convertase subtilisin/kexin Type 9 (PCSK9) gene target nucleic acid sequence, wherein the gRNA is capable of forming a ribonucleoprotein (RNP) with a repressor fusion protein;
- (b) a second nucleic acid encoding a repressor fusion protein, wherein the second nucleic acid is an mRNA, comprising sequences encoding:
- i) a catalytically-dead CRISPR protein;
- ii) a repressor domain (RD1);
- iii) a DNA methyltransferase (DNMT) 3A ATRX-DNMT3-DNMT3L domain (ADD);
- iv) a DNMT3A catalytic domain (DNMT3A);
- and
- v) a DNMT3L domain (DNMT3L).
A method of treating a PCSK9-related disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of a composition comprising:
- (a) a first nucleic acid comprising a guide ribonucleic acid (gRNA) comprising a targeting sequence complementary to a proprotein convertase subtilisin/kexin Type 9 (PCSK9) gene target nucleic acid sequence, wherein the gRNA is capable of forming a ribonucleoprotein (RNP) with a repressor fusion protein;
- (b) a second nucleic acid encoding a repressor fusion protein, wherein the second nucleic acid is an mRNA, comprising sequences encoding:
- i) a catalytically-dead CRISPR protein;
- ii) a repressor domain (RD1);
- iii) a DNA methyltransferase (DNMT) 3A ATRX-DNMT3-DNMT3L domain (ADD);
- iv) a DNMT3A catalytic domain (DNMT3A);
- and
- v) a DNMT3L domain (DNMT3L).
Dependencies are inferred from the claim text.