Ionizable cationic lipids

• US 10,065,919 B2
• Filed: 12/02/2016
• Issued: 09/04/2018
• Est. Priority Date: 03/29/2012
• Status: Active Grant

• Current Assignee: Translate Bio, Inc. (Sanofi )
• Original Assignee: Translate Bio, Inc. (Sanofi )
• Inventors: DeRosa, Frank, Guild, Braydon Charles, Heartlein, Michael
• Primary Examiner(s): Carr, Deborah D
• Application Number:
  US15/368,280
• Publication Number:
  US 20170240501A1
• Time in Patent Office: 641 Days
• Field of Search: 554103
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/21 Monoamines
• CPC Class Codes: C12N 15/85 for animal cells
• CPC Class Codes: C12Y 302/01023 Beta-galactosidase (3.2.1.23), i.e. exo-(1-->4)-beta-D-galactanase

Abstract

Disclosed herein are novel compounds, pharmaceutical compositions comprising such compounds and related methods of their use. The compounds described herein are useful, e.g., as liposomal delivery vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and subsequent transfection of said target cells, and in certain embodiments are characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids.

Claims

1. A lipid nanoparticle comprising a lipid compound having the structure:

2. The lipid nanoparticle of claim 1, comprising one or more polynucleotides.

3. The lipid nanoparticle of claim 2, comprising encapsulated DNA or RNA.

4. The lipid nanoparticle of claim 3, wherein said RNA is mRNA.

5. The lipid nanoparticle of claim 4, wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α

1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α

-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

6. The lipid nanoparticle of claim 1, further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid.

7. The lipid nanoparticle of claim 1, wherein L₁ and L₂ are each an optionally substituted polyunsaturated C₁₈ alkenyl.

8. The lipid nanoparticle of claim 2, wherein said lipid compound is:

9. A lipid nanoparticle comprising a lipid compound having the structure:

10. The lipid nanoparticle of claim 9, comprising one or more polynucleotides.

11. The lipid nanoparticle of claim 10, comprising encapsulated DNA or RNA.

12. The lipid nanoparticle of claim 11, wherein said RNA is mRNA.

13. The lipid nanoparticle of claim 12, wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α

1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α

-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine -4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

14. The lipid nanoparticle of claim 9, further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid.

15. The lipid nanoparticle of claim 9, wherein L₁ and L₂ are each an optionally substituted polyunsaturated C₁₈ alkenyl.

16. A lipid nanoparticle comprising:

a lipid compound having the structure;

17. The lipid nanoparticle of claim 16, comprising encapsulated DNA or RNA.

18. The lipid nanoparticle of claim 17, wherein said RNA is mRNA.

19. The lipid nanoparticle of claim 18, wherein said mRNA encodes a protein or an enzyme selected from the group consisting of human growth hormone, erythropoietin, α

1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α

-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

20. The lipid nanoparticle of claim 16, further comprising one or more lipids selected from the group consisting of a cationic lipid, a neutral lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid.

21. The lipid nanoparticle of claim 16, wherein x is a C₆-₁₀ alkenyl or a C₆-₁₀ alkyl.

22. The lipid nanoparticle of claim 16, wherein said lipid compound is:

23. The lipid nanoparticle of claim 16, wherein said lipid compoud is: