Cleavable lipids

Patent metadata

Field	Value
Publication number	US-11234936-B2
Application number	US-202016790407-A
Country	US
Kind code	B2
Filing date	Feb 13, 2020
Priority date	Jun 8, 2011
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

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 iransfection 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.

First claim

What is claimed is:

1. A nanoparticle comprising
one or more polynucleotides; and
a compound having the structure:

2. The nanoparticle of claim 1 , further comprising one or more compounds selected from the group consisting of a cationic lipid, a PEG-modified lipid, a non-cationic lipid and a helper lipid, wherein
the helper lipid is selected from the group consisting of DSPC (1, 2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1, 2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1, 2-dioleyl-sn-glycero-3-phosphoethanolamine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)), DOPE (1, 2-dioleoyl-snglycero-3-phosphoethanolamine), DSPE (1, 2-distearoyl-sn-glycero-3-phosphoethanolamine), DLPE (I,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPS (1, 2-dipalmitoyl-sn-glycero-3-phospho-L-serine), ceramides, sphingomyelins and cholesterol.

3. The nanoparticle of claim 1 , wherein one or more of the polynucleotides comprises a chemical modification, wherein the chemical modification is selected from the group consisting of:
an end blocking modification of a 5′ or 3′ untranslated region of the mRNA;
a partial sequence of a CMV immediate early 1 gene to the 5′ untranslated region of mRNA;
a poly A tail in the 3′ untranslated region of mRNA;
a Cap1 structure in the 5′ untranslated region of mRNA;
a sequence from the human growth hormone gene to either the 3′ or 5′ untranslated region of the mRNA;
nucleotide analogs;
pendant groups;
a modified polynucleotide base;
one or more substituted nucleotides; and
alteration of one or more codons of a nucleotide.

4. The nanoparticle of claim 1 , wherein the one or more polynucleotides comprise RNA.

5. The nanoparticle of claim 4 , wherein the RNA is mRNA.

6. The nanoparticle of claim 5 , wherein the mRNA is an enzyme MRNA.

7. The nanoparticle of claim 6 , wherein the enzyme is selected from the group consisting of agalsidase alfa, alpha-L-iduronidase, iduronate-2-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, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1).

8. A pharmaceutical composition comprising the nanoparticle of claim 1 .

9. A method of transfecting one or more target cells with a polynucleotide, wherein the method comprises contacting the one or more target cells with the pharmaceutical composition of claim 8 such that the one or more target cells are transfected with the polynucleotide.

10. The nanoparticle of claim 2 , comprising a cationic lipid selected from the group consisting of C12-200, DOTAP (1,2-dioleyl-3-trimethylammonium propane), DODAP (1,2-dioleyl-3-dimethylammonium propane), DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane), DLinDMA (1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane), DLinKC2-DMA (1,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane), HGT4003 (2-((2,3-Bis((9Z, 12Z-octadeca-9,12-dien-1-yloxy)propyl)disulfanyl)-N,N-dimethylethanamine), HGT5001 ((15Z,18Z)—N,N-dimethyl-6-((9Z,12Z-octadeca-9,12-dien-1-yl)tetracosa-4,15,18-trien-1-amine), and ICE (imidazole cholesterol ester).

11. The nanoparticle of claim 2 , comprising one or more PEG-modified lipids, wherein the one or more PEG-modified lipids comprise a polyethyleneglycol chain of up to 5 kDa in length covalently attached to a lipid comprising one or more alkyl chains of C 6 -C 20 in length.

12. The pharmaceutical composition of claim 8 , wherein the nanoparticle comprises mRNA.

13. The nanoparticle of claim 6 , wherein the enzyme is selected from the group consisting of cystic fibrosis transmembrane conductance regulator (CFTR), alpha-L-iduronidase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, and hyaluronidase.

14. The nanoparticle of claim 1 , comprising one or more polynucleotides that is mRNA, and wherein the nanoparticle further comprises one or more non-cationic lipids, one or more helper lipids, and one or more PEG-modified lipids, wherein
the helper lipid is selected from the group consisting of DSPC (1, 2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1, 2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1, 2-dioleyl-sn-glycero-3-phosphoethanolamine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1, 2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)), DOPE (1, 2-dioleoyl-snglycero-3-phosphoethanolamine), DSPE (1, 2-distearoyl-sn-glycero-3-phosphoethanolamine), DLPE (I,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPS (1, 2-dipalmitoyl-sn-glycero-3-phospho-L-serine), ceramides, sphingomyelins and cholesterol.

15. The nanoparticle of claim 14 , wherein the nanoparticle comprises a non-cationic lipid that is a zwitterionic lipid.

16. The nanoparticle of claim 15 , wherein the nanoparticle comprises a helper lipid that is cholesterol.

17. The nanoparticle of claim 16 , wherein the mRNA is an enzyme mRNA selected from the group consisting of cystic fibrosis transmembrane conductance regulator (CFTR), alpha-L-iduronidase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, and hyaluronidase.

18. A compound having the structure:

Assignees

• Translate Bio Inc

Inventors

• Guild Braydon Charles
• Heartlein Michael
• Derosa Frank
• Zhang Jerry Chi

Classifications

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• C12Y302/01022

  Alpha-galactosidase (3.2.1.22) · CPC title

• A61K9/19 Primary

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• C12Y302/01076

  L-Iduronidase (3.2.1.76) · CPC title