Compositions and methods for targeted RNA delivery
Provided herein are compositions, methods of making the same, and methods for targeted delivery of therapeutic agents for modifying expression and function of target genes, e.g. proteins involved in lipid and cholesterol metabolism such as PCSK9. Further provided herein are compositions and methods of treating conditions related to coronary disease.
1. A receptor targeting conjugate, comprising a compound of Formula (V):
wherein,
a plurality of the A groups collectively comprising a receptor targeting ligand;
each of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and L 12 is independently substituted or unsubstituted C 1 -C 12 alkylene, substituted or unsubstituted C 1 -C 12 heteroalkylene, substituted or unsubstituted C 2 -C 12 alkenylene, substituted or unsubstituted C 2 -C 12 alkynylene, —(CH 2 CH 2 O) m —, —(OCH 2 CH 2 ) m —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR 1 )—, —C(═O)—, —C(═N—OR 1 )—, —C(═O)O—, —OC(═O)—, —C(═O)C(═O)—, —C(═O)N(R′)—, —N(R′)C(═O)—, —OC(═O)N(R 1 )—, —N(R 1 )C(═O)O—, —N(R 1 )C(═O)N(R 1 )—, —S(═O) 2 N(R 1 )—, —N(R 1 )S(═O) 2 —, —N(R 1 )—, or —N(OR 1 )—;
L 11 is substituted or unsubstituted —(CH 2 CH 2 O) n — or substituted or unsubstituted —(OCH 2 CH 2 ) n —;
each R 1 is independently H or substituted or unsubstituted C 1 -C 6 alkyl;
R comprises a lipid, nucleic acid, amino acid, protein, or lipid nanoparticle;
m is an integer selected from 1 to 10; and
n is an integer selected from 1 to 200,
wherein each of the A groups is a N-acetylgalactosamine moiety
2. The receptor targeting conjugate of claim 1 , wherein
the plurality of the A groups comprises a lectin receptor targeting ligand;
each of L 1 , L 3 , L 4 , and L 7 comprises —(CH 2 ) 4 —;
each of L 2 , L 5 , and L 8 comprises —C(═O)NH—;
each of L 6 and L 9 comprises —(CH 2 ) 3 —;
L 10 is —(CH 2 ) 1-3 —, —CH 2 CH 2 O— or —CH 2 O—;
L 11 is —(CH 2 CH 2 O) n — or —(OCH 2 CH 2 ) n —, where n is an integer selected from 1 to 50;
L 12 is —NH(CO)O— or —NHC(═O)—; and
R is selected from the group consisting of dialkylglycerolyl, diacylglycerolyl, sterol, n-alkyl comprising C 10 -C 30 carbon atoms, branched alkyl comprising C 10 -C 30 carbon atoms or tocopherol.
3. The receptor targeting conjugate of claim 2 , wherein the n is 1-3, 9-15, 33-39 or 41-49.
4. The receptor targeting conjugate of claim 1 , wherein the receptor targeting conjugate is
5. The receptor targeting conjugate of claim 1 , wherein the R comprises one or more of fatty alcohols, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, polyketides, or sterols or derivatives thereof.
6. The receptor targeting conjugate of claim 1 , wherein the R is a lipid nanoparticle that comprises one or more mRNA encoding one or more gene editor nuclease(s) or base editors and one or more guide RNAs.
7. The receptor targeting conjugate of claim 1 , wherein L 1 , L 4 , and L 7 is independently substituted or unsubstituted C 1 -C 12 alkylene.
8. The receptor targeting conjugate of claim 7 , wherein L 1 , L 4 , and L 7 is independently substituted or unsubstituted C 2 -C 6 alkylene.
9. The receptor targeting conjugate of claim 7 , wherein L 1 , L 4 , and L 7 is C 4 alkylene.
10. The receptor targeting conjugate of claim 1 , wherein each L 2 , L 5 , and L 8 is independently —C(═O)N(R 1 )—, —N(R 1 )C(═O)—, —OC(═O)N(R 1 )—, —N(R 1 )C(═O)O—, or —N(R 1 )C(═O)N(R 1 )—.
11. The receptor targeting conjugate of claim 1 , wherein each L 2 , L 5 , and L 8 is independently —C(═O)N(R 1 )— or —N(R 1 )C(═O)—, wherein R 1 is H or —CH 3 .
12. The receptor targeting conjugate of claim 1 , wherein each L 3 , L 6 , and L 9 is independently substituted or unsubstituted C 1 -C 12 alkylene.
13. The receptor targeting conjugate of claim 12 , wherein each L 3 is substituted or unsubstituted C 2 -C 6 alkylene.
14. The receptor targeting conjugate of claim 1 , wherein each L 6 and L 9 is independently substituted or unsubstituted C 2 -C 10 alkylene.
15. The receptor targeting conjugate of claim 14 , wherein each L 6 and L 9 is independently substituted or unsubstituted C 2 -C 6 alkylene.
16. The receptor targeting conjugate of claim 1 , wherein L 10 is substituted or unsubstituted C 1 -C 12 alkylene.
17. The receptor targeting conjugate of claim 1 , wherein L 11 is —(OCH 2 CH 2 ) n —.
18. The receptor targeting conjugate of claim 17 , wherein n is an integer between 30 and 50.
19. The receptor targeting conjugate of claim 17 , wherein n is 33, 34, 35, 36, 37, 38, or 39.
20. The receptor targeting conjugate of claim 1 , wherein L 12 is —O—, —C(═O)O—, —C(═O)N(R 1 ), —N(R 1 )C(═O)—, or —N(R 1 )C(═O)O—, wherein R 1 is H or —CH 3 .
21. The receptor targeting conjugate of claim 1 , wherein R is a lipid.
22. The receptor targeting conjugate of claim 1 , wherein R is dialkylglycerolyl.
23. The receptor targeting conjugate of claim 1 , wherein A binds to a lectin.
24. The receptor targeting conjugate of claim 1 , wherein
each of L 1 , L 3 , L 4 , and L 7 is —(CH 2 ) 4 —;
each of L 2 , L 5 , and L 8 is —C(═O)NH—;
each of L 6 and L 9 is —(CH 2 ) 3 —;
L 10 : —(CH 2 ) 2 —;
L 11 : —(OCH 2 CH 2 ) n ;
n is 33, 34, 35, 36, 37, 38, or 39;
R is 1,2-O-dioctadecylglycerolyl;
each of the A groups is a N-acetylgalactosamine moiety
and
L 12 is —NH(CO)—.
25. A nanoparticle composition comprising one or more nucleic acid molecular entities and the receptor targeting conjugate of claim 24 .
26. The nanoparticle composition of claim 25 , wherein the one or more nucleic acid molecular entities comprise an mRNA molecule, a guide RNA molecule, or both, wherein the mRNA molecule encodes a gene editor nuclease, a base editor nuclease, or both.
27. A pharmaceutical composition comprising the nanoparticle composition of claim 26 and an excipient or carrier.
28. A receptor targeting conjugate selected from the following:
wherein each of the p and q is independently an integer from 1 to 5, and n is an integer from 1 to 50;
wherein n is an integer from 1 to 50;
wherein each of the p and q is independently an integer from 1 to 5, and n is an integer from 1 to 50;
wherein n is an integer from 1 to 50;
wherein each of the p and q is independently an integer from 1 to 5, and n is an integer from 1 to 50:
wherein each of the p and q is independently an integer from 1 to 5, and n is an integer from 1 to 50;
wherein each of the p and q is independently an integer from 1 to 5, and n is an integer from 1 to 50;
wherein n is an integer from 1-50;