Compositions and methods for organ specific delivery of nucleic acids
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 composition comprising a lipid composition assembled with a therapeutic agent, wherein the lipid composition comprises a cationic selective organ targeting (SORT) lipid in an amount sufficient to yield an apparent pKa of said lipid composition outside a range of about 6 to about 7.
2. The composition of claim 1 , further comprising an ionizable cationic lipid.
3. The composition of claim 1 , wherein said apparent pKa is about 8 or higher.
4. The composition of claim 1 , wherein said apparent pKa is about 6 or lower.
5. The composition of claim 1 , wherein said cationic SORT lipid is present in said lipid composition at a molar percentage from about 5% to about 65%, wherein the molar percentage is determined based on total lipids present in the lipid composition.
6. The composition of claim 1 , wherein said cationic SORT lipid is a permanently cationic SORT lipid.
7. The composition of claim 6 , wherein said permanently cationic SORT lipid comprises a quaternary ammonium ion.
8. The composition of claim 6 , wherein said permanently cationic SORT lipid has a structure of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, stereoisomer, or 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; or
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; or
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.
9. The composition of claim 1 , wherein said cationic SORT lipid is an ionizable cationic SORT lipid.
10. The composition of claim 9 , wherein said ionizable cationic SORT lipid is 1,2-dioleoyl-3-dimethylammonium-propane (DODAP).
11. The composition of claim 1 , wherein said lipid composition comprises said ionizable cationic lipid at a molar percentage from about 5% to about 30%, wherein the molar percentage is determined based on total lipids present in the lipid composition.
12. The composition of claim 1 , wherein said lipid composition further comprises a zwitterionic lipid.
13. The composition of claim 12 , wherein said zwitterionic lipid is a zwitterionic phospholipid.
14. The composition of claim 12 , wherein said lipid composition comprises said zwitterionic lipid at a molar percentage from about 8% to about 23%, wherein the molar percentage is determined based on total lipids present in the lipid composition.
15. The composition of claim 1 , wherein said lipid composition further comprises a polymer-conjugated lipid.
16. The composition of claim 15 , wherein said lipid composition comprises said polymer-conjugated lipid at a molar percentage from about 0.5% to about 10%, wherein the molar percentage is determined based on total lipids present in the lipid composition.
17. The composition of claim 16 , wherein said polymer-conjugated lipid is a poly(ethylene glycol) (PEG)-conjugated lipid.
18. The composition of claim 1 , wherein said lipid composition further comprises a steroid or steroid derivative.
19. The composition of claim 18 , wherein said lipid composition comprises said steroid or steroid derivative at a molar percentage from about 15% to about 46%, wherein the molar percentage is determined based on total lipids present in the lipid composition.
20. The composition of claim 1 , wherein said therapeutic agent comprises one or more members selected from 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, and a CRSIPR-associated (Cas) protein.
21. The composition of claim 1 , wherein said therapeutic agent comprises a messenger ribonucleic acid (mRNA).
22. The composition of claim 1 , wherein said therapeutic agent comprises an RNA molecule that encodes a Cas protein.
23. The composition of claim 22 , wherein said therapeutic agent further comprises a CRISPR-RNA (crRNA), a single guide ribonucleic acid (sgRNA), a trans-activating CRISPR ribonucleic acid (tracrRNA), or a combination thereof.
24. The composition of claim 21 , wherein said therapeutic agent further comprises a single guide polynucleotide.
25. The composition of claim 21 , wherein said therapeutic agent further comprises a double stranded deoxyribonucleic acid (dsDNA), a single stranded deoxyribonucleic acid (ssDNA), or a combination thereof.
26. The composition of claim 1 , wherein said therapeutic agent is present in a ratio of said lipid composition to said therapeutic agent from about 1:1 to about 1:100.
27. The composition of claim 1 , wherein said apparent pKa is about 3 to about 6.
28. The composition of claim 1 , wherein said apparent pKa is about 8 to about 13.
29. The composition of claim 1 , wherein said lipid composition is formulated for delivery of said therapeutic agent to one or more non-liver organs.
30. The composition of claim 29 , wherein said one or more non-liver organs comprise a lung, spleen, a bone marrow, a lymph node, or a combination thereof.