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(12) Patent Application Publication (10) Pub. No.: US 2015/0366997 A1 Guild Et Al US 20150366997A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0366997 A1 Guild et al. (43) Pub. Date: Dec. 24, 2015 (54) COMPOSITIONS AND METHODS FOR MRNA Related U.S. Application Data DELIVERY (60) Provisional application No. 61/734,753, filed on Dec. (71) Applicant: SHIRE HUMANGENETIC 7, 2012. IEER\ries, INC., Lexington, MA Publication Classification (72) Inventors: Braydon Charles Guild, Concord, MA (51) Ek'sMO (2006.01) (US); Frank DeRosa, Chelmsford, MA A647/28 (2006.015 (US); Michael Heartlein, Boxborough, MA (US) A647/24 (2006.01) A647/4 (2006.01) (73) Assignee: Shire Human Genetics Therapies, Inc., (52) U.S. Cl. Lexington, MA (US) CPC ............. A61K 48/0008 (2013.01); A61K 47/14 s (2013.01); A61 K47/28 (2013.01); A61K47/24 (21) Appl. No.: 14/650,104 (2013.01) (22) PCT Filed: Dec. 6, 2013 (57) ABSTRACT (86). PCT No.: PCT/US2013/073672 Disclosed herein are compositions and methods for modulat ing the production of a protein in a target cell. The composi S 371 (c)(1), tions and methods disclosed herein are canablep of ameliorat 2) Date: Jun. 5, 2015 ing9. diseases associated with pprotein or enZVmey deficiencies. Patent Application Publication Dec. 24, 2015 Sheet 1 of 28 US 2015/0366997 A1 Patent Application Publication Dec. 24, 2015 Sheet 2 of 28 US 2015/0366997 A1 Patent Application Publication Dec. 24, 2015 Sheet 3 of 28 US 2015/0366997 A1 Patent Application Publication Dec. 24, 2015 Sheet 4 of 28 US 2015/0366997 A1 Patent Application Publication Dec. 24, 2015 Sheet 5 of 28 US 2015/0366997 A1 Patent Application Publication Dec. 24, 2015 Sheet 6 of 28 US 2015/0366997 A1 9(DIAI Patent Application Publication Dec. 24, 2015 Sheet 7 of 28 US 2015/0366997 A1 (uffii) NOld NWW - NWSW Patent Application Publication Dec. 24, 2015 Sheet 8 of 28 US 2015/0366997 A1 (%) iiiOOLVNHNWSW Patent Application Publication Dec. 24, 2015 Sheet 9 of 28 US 2015/0366997 A1 ?i****Exae, ~*****××××………. *****?? www-a (%) SATOHNWIN Patent Application Publication Dec. 24, 2015 Sheet 10 of 28 US 2015/0366997 A1 //± "tufu) NOdd ASWOSOOWWS) T Patent Application Publication Dec. 24, 2015 Sheet 11 of 28 US 2015/0366997 A1 (tuft/Ouu) AiiA CW WIS) Patent Application Publication Dec. 24, 2015 Sheet 12 of 28 US 2015/0366997 A1 NYS Luiv 8 fu Patent Application Publication Dec. 24, 2015 Sheet 13 of 28 US 2015/0366997 A1 NiOxid ViOiful/Ni Odd WIS 6u Patent Application Publication Dec. 24, 2015 Sheet 14 of 28 US 2015/0366997 A1 WS LuIWS 6. Patent Application Publication Dec. 24, 2015 Sheet 15 of 28 US 2015/0366997 A1 NOdd WO 64!/w8 fiti Patent Application Publication Dec. 24, 2015 Sheet 16 of 28 US 2015/0366997 A1 S. 3 K g s wer saar (ufu) NO waii. NONOO NinjS Patent Application Publication Dec. 24, 2015 Sheet 17 of 28 US 2015/0366997 A1 10000001 Patent Application Publication Dec. 24, 2015 Sheet 18 of 28 US 2015/0366997 A1 |LavaHEMENGD)suNaaldsD(HATIZI 1000001 NiOdd WO 6u/WISW fu Patent Application Publication Dec. 24, 2015 Sheet 19 of 28 US 2015/0366997 A1 co a SC warra .N. r s ver cy N vers C. EC c E. c c s s g ce n s s r &Y. y Patent Application Publication Dec. 24, 2015 Sheet 20 of 28 US 2015/0366997 A1 NiOdd WiO5ui? WS-fu Patent Application Publication Dec. 24, 2015 Sheet 21 of 28 US 2015/0366997 A1 I-III-I, (w) 83S-OSA/CSS GZTWN|F00000Z ON Patent Application Publication Dec. 24, 2015 Sheet 22 of 28 US 2015/0366997 A1 [555-os?t?g?5?. #{}{}{ Oz|5 w) £88-OSA/88S GZiv NiON Patent Application Publication Dec. 24, 2015 Sheet 23 of 28 US 2015/0366997 A1 3${}{} Patent Application Publication Dec. 24, 2015 Sheet 24 of 28 US 2015/0366997 A1 s nze - ... < 59 opS. (f g s 2: is 35. H2 s i. s C i. N. Y s op 2. 3. 3.s - i. an es e. e. e. e. e. g. r C & r N 3 --- Patent Application Publication Dec. 24, 2015 Sheet 25 of 28 US 2015/0366997 A1 NOdd WO 6Lif"WS)-W 5u Patent Application Publication Dec. 24, 2015 Sheet 26 of 28 US 2015/0366997 A1 5is S. 5. is s E. C. c. c a w if r & N. were rers (Tufu) Na3S N. NiOld XI iOi Ovid NV3.N Patent Application Publication Dec. 24, 2015 Sheet 27 of 28 US 2015/0366997 A1 N&StLIWW 6 Patent Application Publication Dec. 24, 2015 Sheet 28 of 28 US 2015/0366997 A1 c rear (uilful) Ndi Odd Odd NWWF US 2015/0366997 A1 Dec. 24, 2015 COMPOSITIONS AND METHODS FOR MIRNA 0004 Another obstacle apparent in these prior approaches DELIVERY at delivery of nucleic acids encoding secreted proteins, is in the levels of protein that are ultimately produced. It is difficult CROSS-REFERENCE TO RELATED to achieve significant levels of the desired protein in the APPLICATIONS blood, and the amounts are not Sustained over time. For 0001. The present application claims priority to U.S. Pro example, the amount of protein produced by nucleic acid visional Application Ser. No. 61/734,753 filed Dec. 7, 2012, delivery does not reach normal physiological levels. See e.g., the disclosure of which is hereby incorporated by reference. US2004/O110709. 0005. In contrast to DNA, the use of RNA as a gene BACKGROUND therapy agent is substantially safer because (1) RNA does not 0002 Novel approaches and therapies are still needed for involve the risk of being stably integrated into the genome of the treatment of protein and enzyme deficiencies. For the transfected cell, thus eliminating the concern that the example, lysosomal storage diseases are a group of approxi introduced genetic material will disrupt the normal function mately 50 rare inherited metabolic disorders that result from ing of an essential gene, or cause a mutation that results in defects in lysosomal function, usually due to a deficiency of deleterious or oncogenic effects; (2) extraneous promoter an enzyme required for metabolism. Fabry disease is a lyso sequences are not required for effective translation of the Somal storage disease that results from a deficiency of the encoded protein, again avoiding possible deleterious side enzyme alpha galactosidase (GLA), which causes a gly effects; (3) in contrast to plasmid DNA (pDNA), messenger colipid known as globotriaosylceramide to accumulate in RNA (mRNA) is devoid of immunogenic CpG motifs so that blood vessels and other tissues, leading to various painful anti-RNA antibodies are not generated; and (4) any deleteri manifestations. For certain diseases, like Fabry disease, there ous effects that do result from mRNA based on gene therapy is a need for replacement of a protein or enzyme that is would be of limited duration due to the relatively short half normally secreted by cells into the blood stream. Therapies, life of RNA. In addition, it is not necessary for mRNA to enter Such as gene therapy, that increase the level or production of the nucleus to perform its function, while DNA must over an affected protein or enzyme could provide a treatment or come this major barrier. even a cure for such disorders. However, there have been several limitations to using conventional gene therapy for this 0006. One reason that mRNA based gene therapy has not purpose. been used more in the past is that mRNA is far less stable than DNA, especially when it reaches the cytoplasm of a cell and 0003 Conventional genetherapy involves the use of DNA is exposed to degrading enzymes. The presence of a hydroxyl for insertion of desired genetic information into host cells. The DNA introduced into the cell is usually integrated to a group on the second carbon of the Sugar moiety in mRNA certain extent into the genome of one or more transfected causes steric hindrance that prevents the mRNA from form cells, allowing for long-lasting action of the introduced ing the more stable double helix structure of DNA and thus genetic material in the host. While there may be substantial makes the mRNA more prone to hydrolytic degradation. As a benefits to Such Sustained action, integration of exogenous result, until recently, it was widely believed that mRNA was DNA into a host genome may also have many deleterious too labile to withstand transfection protocols. Advances in effects. For example, it is possible that the introduced DNA RNA stabilizing modifications have sparked more interest in will be inserted into an intact gene, resulting in a mutation the use of mRNA in place of plasmid DNA in gene therapy. which impedes or even totally eliminates the function of the Certain delivery vehicles, such as cationic lipid or polymer endogenous gene. Thus, genetherapy with DNA may result in delivery vehicles may also help protect the transfected mRNA the impairment of a vital genetic function in the treated host, from endogenous RNases. Yet, in spite of increased stability Such as e.g., elimination or deleteriously reduced production of modified mRNA, delivery of mRNA to cells in vivo in a of an essential enzyme or interruption of a gene critical for the manner allowing for therapeutic levels of protein production regulation of cell growth, resulting in unregulated or cancer is still a challenge, particularly for mRNA encoding full ous cell proliferation. In addition, with conventional DNA length proteins. While delivery of mRNA encoding secreted based gene therapy it is necessary for effective expression of proteins has been contemplated (US2009/0286852), the lev the desired gene product to include a strong promoter els of a full length secreted protein that would actually be sequence, which again may lead to undesirable changes in the produced via in vivo mRNA delivery are not known and there regulation of normal gene expression in the cell.
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