Methods and compositions for modulating plasminogen
The present disclosure provides a duplex or single-stranded siRNA molecule against plasminogen, the siRNA molecule containing modified or unmodified nucleotides and wherein at least one strand of the duplex or the single-stranded siRNA has a sequence that has at least 80% sequence identity to any one of SEQ NOs: 1 to 28. Further provided is a duplex or single-stranded siRNA molecule against plasminogen, the siRNA molecule containing modified or unmodified nucleotides and is between 25 and 35 nucleotides in length. The siRNA molecule may be formulated in a lipid nanoparticle as described herein.
1 . A duplex or single-stranded siRNA molecule against plasminogen mRNA, the siRNA molecule containing modified or unmodified nucleotides and wherein at least one strand of the duplex or the single-stranded siRNA has a sequence that has at least 80% sequence identity to any one of SEQ ID NOs: 1-8 and 15-28.
2 . The duplex or single-stranded siRNA molecule of claim 1 , wherein the siRNA molecule is 20 to 35 nucleotides in length; or
wherein the siRNA molecule is 25 to 35 nucleotides in length.
3 . The siRNA molecule of claim 1 , wherein at least one strand of the sequence has at least 85% sequence identity to any one of SEQ ID NOs: 1-8 and 15-28;
wherein the sequence has at least 90% sequence identity to any one of SEQ ID NOs: 1-8 and 15-28;
wherein the sequence has at least 95% sequence identity to any one of SEQ ID NOs: 1-8 and 15-28;
wherein the sequence has at least 97% sequence identity to any one of SEQ ID Nos: 1 to 28 NOs: 1-8 and 15-28; or
wherein the sequence has at least 98% sequence identity to any one of SEQ ID NOs: 1-8 and 15-28.
4 . The siRNA molecule of claim 3 , wherein the sequence consists essentially of the sequences of any one of SEQ ID Nos. NOs: 1-8 and 15-28.
5 . The siRNA molecule of claim 1 , wherein the sequence is a conjugate molecule.
6 . The siRNA molecule of claim 5 , wherein the conjugate molecule comprises a sugar group.
7 . The siRNA molecule of claim 6 , wherein the sugar group comprises GalNAc.
8 . The siRNA molecule of claim 1 , wherein the sequence has at least 80% sequence identity to any one of SEQ ID NOs: 1-8 or 21-28.
9 . The duplex or single-stranded siRNA molecule of claim 1 , further comprising a lipid nanoparticle.
10 . A lipid nanoparticle comprising:
the duplex or single-stranded siRNA molecule of claim 1 ;
an ionizable, cationic lipid present at between 10 mol % and 85 mol %;
a neutral vesicle-forming lipid selected from at least one of a phospholipid and a triglyceride;
a sterol; and
a hydrophilic polymer-lipid conjugate present at between 0.5 mol % and 5 mol %.
11 . The siRNA molecule of claim 1 further comprising a pharmaceutically acceptable salt; an excipient; or both.
12 . A method of treating a patient having a bleeding disorder comprising administering the siRNA molecule of claim 1 to a patient in need of such treatment thereof.
13 . The method of claim 12 , wherein the bleeding disorder is selected from one or more of: hemophilia A; hemophilia B; von Willebrand Disease (VWD); a platelet disorder; and menorrhagia.
14 . The method of claim 12 , wherein the bleeding disorder is hemophilia A or hemophilia B.
15 . The method of claim 12 , wherein the bleeding disorder is hemophilia A.
16 . The method of claim 12 , wherein the bleeding disorder is hemophilia B.
17 . The method of claim 12 , wherein the bleeding disorder is VWD.
18 . The method of claim 12 , wherein the siRNA molecule stabilizes clots against fibrinolysis; ameliorates bleeding; or both.
19 . The lipid nanoparticle of claim 10 , further comprising a pharmaceutically acceptable salt; an excipient; or both.
20 . An oligonucleotide comprising a contiguous nucleotide sequence of between 10-40, 15-35 or 25-35 nucleotides, wherein the contiguous nucleotide sequence is targeted to hybridize to a sequence selected from the group consisting of SEQ ID NOs: 1-8 or 21-28.