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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/061467 Al 30 April 2015 (30.04.2015) P O P C T (51) International Patent Classification: (72) Inventors: HEARTLEIN, Michael; 300 Shire Way, Lex A61K 48/00 (2006.01) C12N 15/89 (2006.01) ington, Massachusetts 02421 (US). ANDERSON, Daniel; c/o Massachusetts Institute of Technology, 77 Massachu (21) International Application Number: setts Avenue, Cambridge, Massachusetts 02139 (US). PCT/US20 14/06 1793 DONG, Yizhou; c/o Massachusetts Institute of Techno (22) International Filing Date: logy, 77 Massachusetts Avenue, Cambridge, Massachusetts 22 October 2014 (22.10.2014) 02139 (US). DEROSA, Frank; 125 Spring Street, Lexing ton, Massachusetts 02421 (US). (25) Filing Language: English (74) Agents: CHEN, Fangli et al; Choate, Hall & Stewart (26) Publication Language: English LLP, Two International Place, Boston, Massachusetts (30) Priority Data: 021 10 (US). 61/894,299 22 October 20 13 (22. 10.20 13) US (81) Designated States (unless otherwise indicated, for every 61/953,5 16 14 March 2014 (14.03.2014) US kind of national protection available): AE, AG, AL, AM, (71) Applicants: SHIRE HUMAN GENETIC THERAPIES, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, INC. [US/US]; 300 Shire Way, Lexington, Massachusetts BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 0242 1 (US). MASSACHUSETTS INSTITUTE OF DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, Cambridge, Massachusetts 02139 (US). KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [Continued on nextpage] (54) Title: LIPID FORMULATIONS FOR DELIVERY OF MESSENGER RNA (57) Abstract: The present invention provides, among oth er things, methods of delivering mRNA in vivo, including administering to a subject in need of delivery a composi tion comprising an mRNA encoding a protein, encapsu lated within a liposome such that the administering of the composition results in the expression of the protein en coded by the mRNA in vivo, wherein the liposome com prises a cationic lipid of formula I-c: or a pharmaceutically acceptable salt thereof. P © l -c o TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Published: DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, — with international search report (Art. 21(3)) LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, — with sequence listing part of description (Rule 5.2(a)) GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). LIPID FORMULATIONS FOR DELIVERY OF MESSENGER RNA RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Serial No. 61/894,299, filed October 22, 2013 and U.S. Provisional Application Serial No. 61/953,516, filed March 14, 2014, the disclosures of which are hereby incorporated by reference. SEQUENCE LISTING [0002] The present specification makes reference to a Sequence Listing (submitted electronically as a .txt file named "2006685-0687_SL.txt" on October 22, 2014). The .txt file was generated on October 22, 2014 and is 35,552 bytes in size. The entire contents of the Sequence Listing are herein incorporated by reference. BACKGROUND [0003] Delivery of nucleic acids has been explored extensively as a potential therapeutic option for certain disease states. In particular, RNA interference (RNAi) has been the subject of significant research and clinical development. While RNAi, such as short interfering RNA (siRNA), may have therapeutic potential, it is of little use in treating diseases involving deficiency of one or more proteins messenger RNA (mRNA) therapy has become an increasingly important option for treatment of various diseases, in particular, for those associated with deficiency of one or more proteins. SUMMARY OF THE INVENTION [0004] The present invention provides improved methods and compositions for highly efficient delivery and expression of mRNA and encoded protein in vivo. The invention is based, in part, on the surprising discovery that liposomes based on a particular class of cationic lipids, such as, those having a structure of formula I-c described herein, are unexpectedly effective in delivering mRNA and producing encoded protein in vivo, more effective even as compared to those cationic lipids that were considered to be among the best in delivering mRNA in the prior art. Indeed, prior to the present invention, cationic lipids have been extensively explored as an important component of liposomes typically used to encapsulate nucleic acids including mRNA for in vivo delivery. Due to the uniquely fragile and long structure of mRNA and the complicated in vivo translation process, cationic lipids used in the liposomes typically play two roles. First, cationic lipids promote interaction with negatively charged mRNA during encapsulation, circulation and endocytosis, thereby capturing and protecting the mRNA. Then, once inside cytosol, cationic lipids need to be able to release the mRNA so that the mRNA can be translated to produce encoded protein. Some cationic lipids, in particular, those known as titratable cationic lipids are particularly effective in delivering mRNA. One example of such cationic lipids known to be capable of efficient delivery of mRNA is CI2-200. Surprisingly, the present inventors found that cationic lipids described herein can be even more effective in delivering various mRNA in vivo, than those best known in the prior art including C12-200. For example, as shown in the Examples below, liposome particles incorporating a cationic lipid described herein (e.g., cKK-E12) resulted in close to 50% higher protein expression of human Factor IX protein detected in the plasma of administered mice, as compared to C12-200-based liposome particles. Furthermore, the plasma residence time of different proteins expressed from mRNA delivered by cKK-E12 based liposomes is sustained up to 7 days or longer post a single administration. Thus, the present inventors have demonstrated that this class of cationic lipids having a structure of formula I-c described herein (e.g., cKK-E12) can be uniquely useful in delivering mRNA for highly efficient and sustained production of protein (e.g., therapeutic protein) in vivo. The present invention therefore permits an improved mRNA therapy that can significantly reduce required amount of mRNA and associated lipids, administration frequency, and possible side effects, providing more potent, safer, and patient friendly mRNA therapy for various diseases. [0005] In one aspect, the present invention provides methods of delivering messenger RNA (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: l-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 Ci_ alkyl; each instance of R6 and R7 is independently a group of the formula (i), (ii), or (iii); Formulae (i), (ii), and (iii) are: (i) (ii) (iii) 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 NR , wherein R 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; R 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; and L R is optionally substituted Ci_ o alkyl, optionally substituted C2-50 alkenyl, optionally substituted C2-50 alkynyl, optionally substituted heteroCi_so alkyl, optionally substituted heteroC2-5o alkenyl, optionally substituted heteroC2-so alkynyl, or a polymer. [0006] In another aspect, the present invention provides methods of treating a disease or disorder including administering to subject in need of treatment a composition comprising an mRNA encoding a therapeutic protein encapsulated within a liposome such that the administering of the composition results in the expression of the protein encoded by the mRNA in one or more tissues affected by the disease or disorder, wherein the liposome comprises a cationic lipid having a structure of formula I-c. [0007] In another aspect, the present invention provides compositions for delivery of messenger RNA (mRNA) comprising an mRNA encoding a protein encapsulated within a liposome, wherein the liposome comprises a cationic lipid having a structure of formula I-c. [0008] In some embodiments, a suitable cationic lipid is cKK-E12: [0009] In some embodiments, a suitable liposome further comprises one or more non- cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids.
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  • New Mesh Headings for 2018 Single Column After Cutover

    New Mesh Headings for 2018 Single Column After Cutover

    New MeSH Headings for 2018 Listed in alphabetical order with Heading, Scope Note, Annotation (AN), and Tree Locations 2-Hydroxypropyl-beta-cyclodextrin Derivative of beta-cyclodextrin that is used as an excipient for steroid drugs and as a lipid chelator. Tree locations: beta-Cyclodextrins D04.345.103.333.500 D09.301.915.400.375.333.500 D09.698.365.855.400.375.333.500 AAA Domain An approximately 250 amino acid domain common to AAA ATPases and AAA Proteins. It consists of a highly conserved N-terminal P-Loop ATPase subdomain with an alpha-beta-alpha conformation, and a less-conserved C- terminal subdomain with an all alpha conformation. The N-terminal subdomain includes Walker A and Walker B motifs which function in ATP binding and hydrolysis. Tree locations: Amino Acid Motifs G02.111.570.820.709.275.500.913 AAA Proteins A large, highly conserved and functionally diverse superfamily of NTPases and nucleotide-binding proteins that are characterized by a conserved 200 to 250 amino acid nucleotide-binding and catalytic domain, the AAA+ module. They assemble into hexameric ring complexes that function in the energy-dependent remodeling of macromolecules. Members include ATPASES ASSOCIATED WITH DIVERSE CELLULAR ACTIVITIES. Tree locations: Acid Anhydride Hydrolases D08.811.277.040.013 Carrier Proteins D12.776.157.025 Abuse-Deterrent Formulations Drug formulations or delivery systems intended to discourage the abuse of CONTROLLED SUBSTANCES. These may include physical barriers to prevent chewing or crushing the drug; chemical barriers that prevent extraction of psychoactive ingredients; agonist-antagonist combinations to reduce euphoria associated with abuse; aversion, where controlled substances are combined with others that will produce an unpleasant effect if the patient manipulates the dosage form or exceeds the recommended dose; delivery systems that are resistant to abuse such as implants; or combinations of these methods.