Lipid formulations for delivery of messenger RNA
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-048/00
A61K-009/127
A61K-038/53
A61K-038/48
A61K-038/17
출원번호
US-0451312
(2017-03-06)
등록번호
US-10052284
(2018-08-21)
발명자
/ 주소
Heartlein, Michael
Anderson, Daniel
Dong, Yizhou
DeRosa, Frank
출원인 / 주소
TRANSLATE BIO, INC.
대리인 / 주소
Chen, Fangli
인용정보
피인용 횟수 :
0인용 특허 :
184
초록▼
The present invention provides, among other things, methods of delivering mRNA in vivo, including administering to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the expressio
The present invention provides, among other things, methods of delivering mRNA in vivo, including administering to a subject in need of delivery a composition comprising an mRNA encoding a protein, encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in vivo, wherein the liposome comprises a cationic lipid of formula I-c: or a pharmaceutically acceptable salt thereof.
대표청구항▼
1. A method of treating cystic fibrosis comprising administering to subject in need of treatment a composition comprising an mRNA encoding a cystic fibrosis transmembrane conductance regulator (CFTR) protein encapsulated within a liposome such that the administering of the composition results in the
1. A method of treating cystic fibrosis comprising administering to subject in need of treatment a composition comprising an mRNA encoding a cystic fibrosis transmembrane conductance regulator (CFTR) protein encapsulated within a liposome such that the administering of the composition results in the expression of the CFTR protein encoded by the mRNA in one or more tissues affected by cystic fibrosis;wherein the liposome comprises a cationic lipid of formula I-c: or a pharmaceutically acceptable salt thereof,wherein:p is an integer of between 1 and 9, inclusive;each instance of R2 is independently hydrogen or optionally substituted C1-6 alkyl;each instance of R6 and R7 is independently a group of the formula (i), (ii), or (iii);Formulae (i), (ii), and (iii) are: wherein: each instance of R′ is independently hydrogen or optionally substituted alkyl;X is O, S, or NRX, wherein RX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;Y is O, S, or NRY, wherein RY is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;RP is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; andRL is optionally substituted C1-50 alkyl, optionally substituted C2-50 alkenyl, optionally substituted C2-50 alkynyl, optionally substituted heteroC1-50 alkyl, optionally substituted heteroC2-50 alkenyl, optionally substituted heteroC2-50 alkynyl, or a polymer. 2. The method of claim 1, wherein the cationic lipid is cKK-E12: 3. The method of claim 1, wherein the liposome further comprises one or more non-cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids. 4. The method of claim 3, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine) DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)). 5. The method of claim 3, wherein the one or more cholesterol-based lipids are cholesterol and/or PEGylated cholesterol. 6. The method of claim 3, wherein the liposome comprises cKK-E12, DOPE, cholesterol and DMG-PEG2K. 7. The method claim 1, wherein the liposome has a size less than about 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, or 50 nm. 8. The method of claim 1, wherein the mRNA comprises one or more modified nucleotides, and wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine. 9. The method of claim 1, wherein the mRNA is unmodified.
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