Cleavable Lipids
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.
1 . A nanoparticle comprising
one or more polynucleotides;
and
a compound having the structure:
wherein R 1 imidazole or guanidinium;
wherein R 2 is
and
wherein n is zero, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty.
2 . (canceled)
3 . The nanoparticle of claim 1 , wherein R 1 is imidazole.
4 . The nanoparticle of claim 1 , wherein
R 1 is imidazole;
and
n is 1.
5 . The nanoparticle of claim 1 , wherein R 1 is guanidinium.
6 . The nanoparticle-of claim 1 , wherein
R 1 is guanidinium;
and
n is 1.
7 .- 23 . (canceled)
24 . The nanoparticle of claim 1 , comprising a compound having the structure:
25 . The nanoparticle of claim 1 , comprising a compound having the structure:
26 .- 29 . (canceled)
30 . 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.
31 . (canceled)
32 . The nanoparticle of claim 1 , wherein one or more of the polynucleotides comprises a chemical modification.
33 . The nanoparticle of claim 1 , wherein the one or more polynucleotides is selected from the group consisting of an antisense oligonucleotide, siRNA, miRNA, snRNA, snoRNA and combinations thereof.
34 . (canceled)
35 . The nanoparticle of claim 1 , wherein the one or more polynucleotides comprise DNA.
36 . The nanoparticle of claim 1 , wherein the one or more polynucleotides comprise RNA.
37 . (canceled)
38 . The nanoparticle of claim 36 , wherein the RNA encodes an enzyme.
39 . The nanoparticle of claim 38 , 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).
40 . A pharmaceutical composition comprising the nanoparticle of claim 1 .
41 . A method of treating disease in a subject, wherein the method comprises administering an effective amount of the pharmaceutical composition of claim 40 to the subject.
42 . 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 40 such that the one or more target cells are transfected with the polynucleotide.
43 .- 68 . (canceled)
69 . The nanoparticle of claim 36 , wherein the RNA comprises mRNA.
70 . The nanoparticle of claim 69 , wherein the mRNA is modified to improve stability.
71 . The nanoparticle of claim 30 , wherein the one or more cationic lipids are 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-l-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).
72 . The nanoparticle of claim 30 , further 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.
73 . The pharmaceutical composition of claim 40 , wherein the nanoparticle comprises mRNA.
74 . The nanoparticle of claim 38 , 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.