(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 2015/051214 Al 9 April 2015 (09.04.2015) W P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07K 14/705 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 14/058967 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 3 October 2014 (03. 10.2014) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English 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. (30) Priority Data: 61/886,137 3 October 201 3 (03. 10.2013) US (84) Designated States (unless otherwise indicated, for every 61/903,485 13 November 2013 (13. 11.2013) US kind of regional protection available): ARIPO (BW, GH, 61/952,906 14 March 2014 (14.03.2014) us GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/052,139 18 September 2014 (18.09.2014) us TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: MODERNA THERAPEUTICS, INC. DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [US/US]; 200 Technology Square, Cambridge, Massachu LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, setts 02 139 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: ELLSWORTH, Jeff Lynn; 23 Meriam Street, Lexington, Massachusetts 02420 (US). BOLEN, Joseph Published: Beene; 1 Avery Street, 29B, Boston, Massachusetts 021 11 — with international search report (Art. 21(3)) (US). GREGOIRE, Francine M.; 184 Austin Street SI, Newton, Massachusetts 02465 (US). GUILD, Justin; 495 — before the expiration of the time limit for amending the Edgell Rd, Framingham, Massachusetts 01701 (US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (74) Agents: WARD, Donna T. et al: 142A Main Street, Gro- ton, Massachusetts 01450 (US). — with sequence listing part of description (Rule 5.2(a)) (54) Title: POLYNUCLEOTIDES ENCODING LOW DENSITY LIPOPROTEIN RECEPTOR Mouse LD L WT Mouse LD R mutant © - (57) Abstract: The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynuc - leotide molecules encoding low density lipoprotein receptor comprising at least one mutation (e.g., an LDLR signally enhancing o mutation). POLYNUCLEOTIDES ENCODING LOW DENSITY LIPOPROTEIN RECEPTOR CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 62/052,139 filed September 18, 2014, entitled Polynucleotides Encoding Low Density Lipoprotein Receptor, U.S. Provisional Patent Application No. 61/952,906, filed March 14, 2014, entitled Polynucleotides Encoding Low Density Lipoprotein Receptor, U.S. Provisional Patent Application No. 61/886,137, filed October 3, 2013, entitled Polynucleotides Encoding Low Density Lipoprotein Receptor and U.S. Provisional Patent Application No. 61/903,485, filed November 13, 2013, entitled Polynucleotides Encoding Low Density Lipoprotein Receptor, the contents of each of which are herein incorporated by reference in its entirety. REFERENCE TO SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled M070PCT.txt, created on October 3, 2014 which is 2,607,599 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0003] The invention relates to compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of polynucleotides encoding low density lipoprotein receptor comprising at least one mutation, e.g., a LDLR cell surface expression-enhancing mutation, a mutation increasing the residence time of LDLR at the cell surface or a mutation resulting in increased levels of LDLR at the cell surface. BACKGROUND OF THE INVENTION [0004] High cholesterol is one of a number of risk factors for heart attack and stroke. Although poor diet and lack of excise are common causes of high cholesterol, genetic changes, such as familiar hypercholesterolemia (FH), which is caused by deficiency in LDLR, can be causes of high cholesterol. A number of cholesterol lowering drugs are currently on the market but they are not without risk or contraindications with certain conditions or other medications. Such drugs include statins, fibrates, niacin, bile acid sequestrants (resins), phytosterols, or other compounds that prevent absorption of fats, reduce absorption of cholesterol, or target genes in the cholesterol trafficking pathway. [0005] Nucleic acid based cholesterol lowering drugs include, for example an antisense oligonucleotide inhibitor which targets ApoB-100, mipomersen, which was approved in January 2013 for the treatment of homozygous familial hypercholesterolemia (FH). In December of 2012, the FDA also approved lomitapide for the same condition. [0006] More troubling are the liver related problems associated with cholesterol targeting drugs, particularly elevation in serum transaminases and accumulation of hepatic fat (or hepatic steatosis). For example, because of the potentially significant safety concerns surrounding mipomersen, the drug will carry a boxed warning about liver toxicity as well as requiring certification of prescribers and pharmacies, as well as documentation that the drug is being properly used with each new prescription. While mipomersen was generally effective in lowering LDL cholesterol (more than half of patients in clinical trials had more than a 20% decrease in LDL levels and in the homozygous FH trial, it reduced LDL by 24.7%), a typical FH patient has an average LDL between 400-1000mg/dL. Consequently, lowering was not likely enough in these patients. In addition, the trials were not large enough to be powered to assess cardiovascular outcomes, though cardiovascular benefit is of course the ultimate intended effect of the drug. Further, serious adverse events of cardiac disorders occurred in the mipomersen group in phase 3 trials. [0007] The present invention addresses the problem of the degradation of LDLR by providing polynucleotides which encode a polypeptide of interest comprising at least one mutation, e.g., a LDLR cell surface expression-enhancing mutation, a mutation increasing the residence time of LDLR at the cell surface or a mutation resulting in increased levels of LDLR at the cell surface. The present invention addresses this need by providing nucleic acid based compounds or polynucleotides (both coding and non- coding and combinations thereof) which have structural and/or chemical features that avoid one or more of the problems in the art, for example, features which are useful for optimizing nucleic acid-based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, improving expression rates, half life and/or protein concentrations, optimizing protein localization, and avoiding deleterious bio-responses such as the immune response and/or degradation pathways. These barriers may be reduced or eliminated using the present invention. SUMMARY OF THE INVENTION [0008] Described herein are compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of polynucleotides encoding low density lipoprotein receptor (LDLR) comprising at least one mutation, e.g., a LDLR cell surface expression-enhancing mutation, a mutation increasing the residence time of LDLR at the cell surface or a mutation resulting in increased levels of LDLR at the cell surface. In one nonlimiting embodiment, such polynucleotides take the form or or function as modified mRNA molecules which encode one or more peptides or polypeptides of interest. In one embodiment, such polynucleotides are substantially non- coding. [0009] Provided herein are polynucleotides encoding LDLR. In one aspect the polynucleotides comprise at least one chemical modified nucleoside disclosed herein such as naturally and non-naturally occurring nucleosides. [0010] In one embodiment, provided herein are polynucleotides, e.g., IVT polynucleotides for the expression of LDLR comprising a first region of linked nucleosides, a first flanking region located 5' relative to the first region and a second flanking region located 3' relative to the first region. The first region may encode a polypeptide of interest encoding LDLR such as, but not limited to, SEQ ID NO: 37-55. The first region of linked nucleosides may comprise at least an open reading frame of a nucleic acid sequence such as, but not limited to, SEQ ID NO: 56-718. [0011] In one embodiment, provided herein are polynucleotides, e.g., IVT polynucleotides for the expression of LDLR comprising a first region of linked nucleosides, a first flanking region located 5' relative to the first region and a second flanking region located 3' relative to the first region. The first region may encode a polypeptide of interest encoding LDLR such as, but not limited to, SEQ ID NO: 37-55. The first region of linked nucleosides may comprise at least an open reading frame of a nucleic acid sequence such as, but not limited to, SEQ ID NO: 56-718. [0012] In one embodiment, the polynucleotides e.g., IVT polynucleotides described herein may encode a polypeptide of interest comprising at least two mutations, e.g., a LDLR cell surface expression-enhancing mutation, a mutation increasing the residence time of LDLR at the cell surface or a mutation resulting in increased levels of LDLR at the cell surface.