Compositions and methods for organ specific delivery of nucleic acids
View Patent ↗The present disclosure provides compositions which shown preferential targeting or delivery of a nucleic acid composition to a particular organ. In some embodiments, the composition comprises a steroid or sterol, an ionizable cationic lipid, a phospholipid, a PEG lipid, and a permanently cationic lipid which may be used to deliver a nucleic acid.
1. A method for targeted delivery of a therapeutic agent to a non-liver organ or a non-liver cell therein in a subject in need thereof, the method comprising:
administering to said subject said therapeutic agent assembled with a selective organ targeting (SORT) lipid composition that comprises:
an ionizable cationic lipid; and
a SORT lipid separate from said ionizable cationic lipid, which SORT lipid is selected from the group consisting of a cationic SORT lipid, a zwitterionic SORT lipid, and an anionic SORT lipid,
wherein said SORT lipid composition is characterized by an apparent ionization constant (pKa) outside a range of about 6 to about 7 as determined by a 2-(p-toluidino)-6-naphthalenesulfonic acid titration assay,
thereby providing a greater amount or activity of said therapeutic agent in said non-liver organ or said non-liver cell therein in said subject as compared to that achieved absent said SORT lipid.
2. The method of claim 1 , wherein said pKa of said SORT lipid composition is of about 8 or higher, or of about 6 or lower.
3. The method of claim 1 , wherein said non-liver organ is a lung, or spleen; or wherein said non-liver cell is a lung cell, or a spleen cell.
4. The method of claim 1 , wherein said SORT lipid is present in said SORT lipid composition at a molar percentage from about 5% to about 65%.
5. The method of claim 1 , wherein said SORT lipid is present in said SORT lipid composition at a molar percentage from about 5% to about 50%.
6. The method of claim 1 , wherein said cationic SORT lipid is a permanently cationic SORT lipid comprising a quaternary ammonium ion.
7. The method of claim 1 , wherein said cationic SORT lipid is a permanently cationic SORT lipid having a structure of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
wherein, in Formula (I):
R 1 and R 2 are each independently alkyl (C8-C24) , alkenyl (C8-C24) , or a substituted version of either group;
R 3 , R 3 ′, and R 3 ′″ are each independently alkyl (C≤6) or substituted alkyl (C≤6) ; and
X − is a monovalent anion;
wherein, in Formula (II):
R 4 and R 4 ′ are each independently alkyl (C6-C24) , alkenyl (C6-C24) , or a substituted version of either group;
R 4 ″ is alkyl (C≤24) , alkenyl (C≤24) , or a substituted version of either group;
R 4 ′″ is alkyl (C1-C8) , alkenyl (C2-C8) , or a substituted version of either group; and
X 2 is a monovalent anion; and
wherein, in Formula (III):
R 1 and R 2 are each independently alkyl (C8-C24) , alkenyl (C8-C24) , or a substituted version of either group;
R 3 , R 3 ′, and R 3 ″ are each independently alkyl (C≤6) or substituted alkyl (C≤6) ;
R 4 is alkyl (C≤6) or substituted alkyl (c<6) ; and
X − is a monovalent anion.
8. The method of claim 1 , wherein said zwitterionic SORT lipid is a zwitterionic phospholipid.
9. The method of claim 1 , wherein said anionic SORT lipid comprises a phosphate group.
10. The method of claim 1 , wherein said anionic SORT lipid has a structure of Formula (IV):
wherein, in Formula (IV):
R 1 and R 2 are each independently alkyl (C8-C24) , alkenyl (C8-C24) , or a substituted version of either group;
R 3 is hydrogen, alkyl (C≤6) , or substituted alkyl (C≤6) , or -Y 1 -R 4 , wherein:
Y 1 is alkanediyl (C≤6) or substituted alkanediyl (C≤6) ; and
R 4 is acyloxy (C≤8-24) or substituted acyloxy (C≤8-24) .
11. The method of claim 1 , wherein said SORT lipid composition further comprises a phospholipid, a polymer-conjugated lipid, a steroid or steroid derivative, or a combination thereof separate from said SORT lipid.
12. The method of claim 1 , wherein said ionizable cationic lipid separate from said SORT lipid is present in said SORT lipid composition at a molar percentage from about 5% to about 30%.
13. The method of claim 11 , wherein said phospholipid separate from said SORT lipid is present in said SORT lipid composition at a molar percentage from about 8% to about 23%.
14. The method of claim 11 , wherein said polymer-conjugated lipid separate from said SORT lipid is present in said SORT lipid composition at a molar percentage from about 0.5% to about 10%.
15. The method of claim 11 , wherein said steroid or steroid derivative separate from said SORT lipid is present in said SORT lipid composition at a molar percentage from about 15% to about 46%.
16. The method of claim 1 , wherein said therapeutic agent comprises a small interfering ribonucleic acid (siRNA), a micro-ribonucleic acid (miRNA), a primary micro-ribonucleic acid (pri-miRNA), a messenger ribonucleic acid (mRNA), a clustered regularly interspaced short palindromic repeats (CRISPR) related nucleic acid, a CRISPR-RNA (crRNA), a single guide ribonucleic acid (sgRNA), a trans-activating CRISPR ribonucleic acid (tracrRNA), a plasmid deoxyribonucleic acid (pDNA), a transfer ribonucleic acid (tRNA), an antisense oligonucleotide (ASO), a guide ribonucleic acid, a double stranded deoxyribonucleic acid (dsDNA), a single stranded deoxyribonucleic acid (ssDNA), a single stranded ribonucleic acid (ssRNA), a double stranded ribonucleic acid (dsRNA), a protein, a CRSIPR-associated (Cas) protein, or a combination thereof.
17. The method of claim 1 , wherein said therapeutic agent is present in a ratio of said therapeutic agent to said SORT lipid composition from about 1:1 to about 1:100.
18. A method for targeted delivery of a therapeutic agent to a non-liver organ or a non-liver cell of a subject, the method comprising:
administering to said subject said therapeutic agent assembled with a selective organ targeting (SORT) lipid composition that comprises:
an ionizable cationic lipid, and
a cationic SORT lipid,
thereby providing a greater amount or activity of said therapeutic agent in said non-liver organ or said non-liver cell in said subject as compared to that achieved absent said cationic SORT lipid.
19. The method of claim 18 , wherein said non-liver organ is a lung; or wherein said non-liver cell is a lung cell.
20. The method of claim 18 , wherein said cationic SORT lipid is a permanently cationic SORT lipid.
21. The method of claim 18 , wherein said permanently cationic SORT lipid comprises a quaternary ammonium ion.
22. The method of claim 21 , wherein said permanently cationic SORT lipid has a structure of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
wherein, in Formula (I):
R 1 and R 2 are each independently alkyl (C8-C24) , alkenyl (C8-C24) , or a substituted version of either group;
R 3 , R 3 ′, and R 3 ″ are each independently alkyl(C≤6) or substituted alkyl(C≤6); and
X − is a monovalent anion;
wherein, in Formula (II):
R 4 and R 4 ′ are each independently alkyl (C6-C24) , alkenyl (C6-C24) , or a substituted version of either group;
R 4 ″ is alkyl (C≤24) , alkenyl (C≤24) , or a substituted version of either group;
R 4 ′″ is alkyl (C1-C8) , alkenyl (C2-C8) , or a substituted version of either group; and
X 2 is a monovalent anion; and
wherein, in Formula (III):
R 1 and R 2 are each independently alkyl (C8-C24) , alkenyl (C8-C24) , or a substituted version of either group;
R 3 , R 3 ′, and R 3 ″ are each independently alkyl (C≤6) or substituted alkyl (C≤6) ;
R 4 is alkyl (C≤6) or substituted alkyl (C≤6) ; and
X − is a monovalent anion.
23. The method of claim 18 , wherein said cationic SORT lipid is an ionizable cationic SORT lipid.
24. The method of claim 23 , wherein said ionizable cationic SORT lipid is 1,2-dioleoyl-3-dimethylammonium-propane (DODAP).
25. The method of claim 18 , wherein said cationic SORT lipid is present in said SORT lipid composition at a molar percentage from about 5% to about 65%.
26. The method of claim 18 , wherein said SORT lipid composition further comprises a phospholipid, a polymer-conjugated lipid, a steroid or steroid derivative, or a combination thereof separate from said cationic SORT lipid.
27. The method of claim 18 , wherein said therapeutic agent comprises a small interfering ribonucleic acid (siRNA), a micro-ribonucleic acid (miRNA), a primary micro-ribonucleic acid (pri-miRNA), a messenger ribonucleic acid (mRNA), a clustered regularly interspaced short palindromic repeats (CRISPR) related nucleic acid, a CRISPR-RNA (crRNA), a single guide ribonucleic acid (sgRNA), a trans-activating CRISPR ribonucleic acid (tracrRNA), a plasmid deoxyribonucleic acid (pDNA), a transfer ribonucleic acid (tRNA), an antisense oligonucleotide (ASO), a guide ribonucleic acid, a double stranded deoxyribonucleic acid (dsDNA), a single stranded deoxyribonucleic acid (ssDNA), a single stranded ribonucleic acid (ssRNA), a double stranded ribonucleic acid (dsRNA), a protein, a CRSIPR-associated (Cas) protein, or a combination thereof.
28. The method of claim 18 , wherein said SORT lipid composition is characterized by an apparent ionization constant (pKa) of about 8 to about 13 as determined by a 2-(p-toluidino)-6-naphthalenesulfonic acid titration assay.
29. The method of claim 18 , wherein said SORT lipid composition is characterized by an apparent ionization constant (pKa) of about 9 or higher as determined by a 2-(p-toluidino)-6-naphthalenesulfonic acid titration assay.
30. The method of claim 18 , wherein said SORT lipid composition is characterized by an apparent ionization constant (pKa) of about 3 to about 6 as determined by a 2-(p-toluidino)-6-naphthalenesulfonic acid titration assay.
31. The method of claim 1 , wherein said pKa of said SORT lipid composition is of about 8 or higher.
32. The method of claim 1 , wherein said pKa of said SORT lipid composition is of about 8 to about 13.
33. The method of claim 1 , wherein said pKa of said SORT lipid composition is of about 9 or higher.
34. The method of claim 18 , wherein said administering comprises systemic administration.
35. The method of claim 18 , wherein said administering comprises intravenous administration.
36. The method of claim 1 , wherein said administering comprises systemic administration.
37. The method of claim 1 , wherein said administering comprises intravenous administration.
38. The method of claim 1 , wherein said non-liver organ is a lung, or wherein said non-liver cell is a lung cell.
39. The method of claim 1 , wherein said non-liver organ is spleen, or wherein said non-liver cell is a spleen cell.