Cystine cationic lipids
The present invention provides, in part cystine cationic lipid compounds of formula A, and sub-formulas thereof: or a pharmaceutically acceptable salt thereof. The compounds provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.
1 . A cationic lipid having the following structure:
or a pharmaceutically acceptable salt thereof,
wherein
each R 1a is independently hydrogen, R 1c , or R 1d ,
each R 1b is independently R 1c or R 1d ,
each R 1c is independently —(CH 2 ) 2 C(O)X 1 R 3 ;
each R 1d is independently —C(O)R 4 ;
each R 2 is independently —[C (R 2a ) 2 ] c R 2b ;
each R 2a is independently hydrogen or C 1 -C 6 alkyl;
R 2b is —(OCH 2 CH 2 ) b OH or —(OCH 2 CH 2 ) b OCH 3 ;
each R 3 is independently C 6 -C 30 aliphatic;
each R 4 is independently unsubstituted C 6 -C 24 alkyl or C 6 -C 10 alkyl substituted with —OC(O)R 5 or —CO 2 R 5 , wherein R 5 is unsubstituted C 6 -C 16 alkyl;
each X 1 is independently a covalent bond or O;
each a is independently an integer of 1-10;
each b is independently an integer of 1-10; and
each c is independently an integer of 1-10.
2 . The cationic lipid of claim 1 , wherein
each a is 1 or 2;
each R 1a and R 1b is —(CH 2 ) 2 C(O)X 1 R 3 ; or
each R 1a is hydrogen and each R 1b is —C(O)R 4 .
3 . The cationic lipid of claim 2 , having the following structure:
or a pharmaceutically acceptable salt thereof.
4 . The cationic lipid of claim 2 , having the following structure:
or a pharmaceutically acceptable salt thereof.
5 . The cationic lipid of claim 1 , wherein each c is 2, 3, or 4.
6 . The cationic lipid of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7 . A composition comprising a nucleic acid encapsulated within a liposome, wherein the liposome comprises a cationic lipid according to claim 1 .
8 . The composition of claim 7 , wherein the nucleic acid is an mRNA encoding a peptide or protein.
9 . The composition of claim 8 , wherein the mRNA encodes a peptide or protein for use in vaccine.
10 . The composition of claim 9 , wherein the mRNA encodes an antigen.
11 . A liposomal composition comprising the compound of claim 1 .
12 . The liposomal composition of claim 11 , further comprising one or more of a PEG-modified lipid, a non-cationic lipid and a cholesterol lipid.
13 . The composition of claim 7 , wherein said composition is a pharmaceutical composition.
14 . The composition of claim 8 , wherein said mRNA encodes a therapeutic protein.
15 . A method of treating a disease in a subject comprising administering to the subject a composition of claim 14 .
16 . The method of claim 15 , wherein said disease is associated with deficiency of one or more proteins.