Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , a, b, c, d and e are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
1. A method for inducing expression of a protein in a subject, comprising administering to the subject a lipid nanoparticle comprising:
i) a compound having the following structure (II):
wherein:
R 10 and R 11 are each independently a straight, saturated alkyl chain containing from 12 to 16 carbon atoms; and
z is selected such that the polyethyleneglycol (PEG) portion,
of structure (II) has an average molecular weight of about 2000 to 6000 g/mol; and
ii) an mRNA encoding the protein.
2. The method of claim 1 , wherein expression of the protein induces a pharmacological effect in the subject.
3. The method of claim 2 , wherein the pharmacological effect is increased production of red blood cells.
4. The method of claim 2 , wherein the pharmacological effect is protection against infection by an infectious agent.
5. The method of claim 4 , wherein the infectious agent is a virus.
6. The method of claim 1 , wherein the mRNA encodes an antibody.
7. The method of claim 1 , wherein the protein is expressed in the subject's liver.
8. The method of claim 1 , wherein the subject is a mammal.
9. The method of claim 1 , wherein the subject is a non-human primate.
10. The method of claim 1 , wherein the subject is a human.
11. The method of claim 1 , wherein R 10 and R 11 are each straight, saturated alkyl chains containing 12 carbon atoms.
12. The method of claim 1 , wherein R 10 and R 11 are each straight, saturated alkyl chains containing 14 carbon atoms.
13. The method of claim 1 , wherein R 10 and R 11 are each straight, saturated alkyl chains containing 16 carbon atoms.
14. The method of claim 1 , wherein z ranges from 30 to 60.
15. The method of claim 1 , wherein z is 45.
16. The method of claim 1 , wherein z is selected such that an average molecular weight of structure (II) is about 2500 g/mol.
17. The method of claim 1 , having the following structure:
wherein n ranges from 40 to 50.
18. The method of claim 17 , wherein n is 45.
19. The method of claim 1 , having the following structure:
wherein n is selected such that an average molecular weight of the compound is about 2500 g/mol.
20. The method of claim 1 , having the following structure:
wherein n ranges from 40 to 50.
21. The method of claim 20 , wherein n is 45.
22. The method of claim 1 , having the following structure:
wherein n is selected such that an average molecular weight of the compound is about 2500 g/mol.
23. The method of claim 1 , having the following structure:
wherein n ranges from 40 to 50.
24. The method of claim 23 , wherein n is 45.
25. The method of claim 1 , having the following structure:
wherein n is selected such that an average molecular weight of the compound is about 2500 g/mol.