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(12) United States Patent (10) Patent No.: US 8,883,506 B2 Rossi Et Al

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(12) United States Patent (10) Patent No.: US 8,883,506 B2 Rossi Et Al USOO88835 06B2 (12) United States Patent (10) Patent No.: US 8,883,506 B2 Rossi et al. (45) Date of Patent: *Nov. 11, 2014 (54) KITS COMPRISING LINEAR DNAS FOR FOREIGN PATENT DOCUMENTS SUSTAINED POLYPEPTIDE EXPRESSION EP 219 1840 * 6, 2010 USING SYNTHETIC, MODIFIED RNAS WO 2009,077134 6, 2009 WO WO 2009,077134 * 6/2009 (75) Inventors: Derrick Rossi, Roslindale, MA (US); WO WO2010/033906 * 3/2010 Luigi Warren, Cambridge, MA (US) WO WO2O10O33906 * 3/2010 WO WO2O10,042490 * 4, 2010 WO WO2O100.42490 * 4, 2010 (73) Assignee: Children's Medical Center WO 2010/105257 9, 2010 Corporation, Boston, MA (US) WO WO2O110O8956 * 1 2011 WO 2011, 130624 10, 2011 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 41 days. Moore (2002, DNA and Cell Biol., vol. 21(5/6), pp. 443-451).* This patent is Subject to a terminal dis Thomson (1995, PNAS, vol. 92, pp. 7844-7848).* claimer. NIH (Stem Cells: Scientific Progress and Future Research Direc tions, Department of Health and Human Services, Chapter 1, Jun. 2001).* (21) Appl. No.: 13/590,902 NIH (Stem Cells: Scientific Progress and Future Research Direc tions, Department of Health and Human Services, Chapter 3, Jun. (22) Filed: Aug. 21, 2012 2001).* Takahashi (Cell, 2006, vol. 126:663-676).* (65) Prior Publication Data Yu (Science, Nov. 20, 2007, vol. 318, p. 1917-1920).* US 2012/0322865A1 Dec. 20, 2012 Blelloch (Cell Stem Cell, Sep. 13, 2007, vol. 1, p. 245-247).* Nakagawa (Nat Biotechnol. 2008, vol. 26: 101-106).* Sequence search notes, 2012.* Yisraeli (Methods in Enzymology, 1989, vol. 180, p. 42-50).* Related U.S. Application Data Kariko (Mol. Ther. Nov. 2008, vol. 16, No. 11, p. 1833-1840).* (63) Continuation of application No. 13/088,009, filed on Hoheisel et al., J. Biol. Chem., 1990, 265, 16656.* Apr. 15, 2011, now Pat. No. 8,802,438. Zhou et al., Cell Stem Cell, 4(5):381-4 (2009). “Generation of induced pluripotent stem cells using recombinant proteins.” (60) Provisional application No. 61/325,003, filed on Apr. Warren et al., Cell Stem Cell, 7:618-630 (2010). “Highly efficient 16, 2010, provisional application No. 61/387,220, reprogramming to pluripotency and directed differentiation of filed on Sep. 28, 2010. human cells with synthetic modified mRNA.” Angel et al., PLoS ONE, 5(7):el 1756 (2010). "Innate immune Sup (51) Int. Cl. pression enables frequent transfection with RNA encoding repro CI2N IS/00 (2006.01) gramming proteins.” C7H 2L/02 (2006.01) Audouy and Hoekstra, Mol. Membr. Biol. 18:129-143 (2001). (52) U.S. Cl. “Cationic lipid-mediated transfection in vitro and in vivo..” USPC .......................................... 435/455:536/23.1 Chan E.M.et al., Nat. Biotechnol. 27(11): 1033-1037 (2009). “Live cell imaging distinguishes bona fide human iPS cells from partially (58) Field of Classification Search reprogrammed cells.” USPC .......................................... 536/23.1; 435/455 Chang et al., Stem Cells, 27(5):1042-1049 (2009). “Polycistronic See application file for complete search history. lentiviral vector for hit and run reprogramming of adult skin fibro (56) References Cited blasts to induced pluripotent stem cells.” U.S. PATENT DOCUMENTS (Continued) 5,466,584. A * 1 1/1995 Tanizawa et al. ............ 435/69.1 Primary Examiner — Michael C. Wilson 5,955,443 A * 9/1999 Bennett et al. .. 514.f44 A (74) Attorney, Agent, or Firm — Nixon Peabody, LLP: 8, 158,415 B2 * 4/2012 Jo et al. ........ 435/320.1 David S. Resnick; Leena H. Karttunen Contarino 8,211,656 B2 * 7/2012 Hyde et al. ... 435/721 8,211,697 B2 * 7/2012 Sakurada et al. 435/377 8,257,941 B2* 9/2012 Sakurada et al. 435/29 (57) ABSTRACT 8,273,570 B2 * 9/2012 Sasai et al. ............. ... 435,368 Described herein are synthetic, modified RNAs for changing 8,664,194 B2 * 3/2014 de Fougerolles et al. ... 514/44 R 2004/025.3606 A1* 12/2004 Aziz et al. ......................... 435/6 the phenotype of a cell. Such as expressing a polypeptide or 2006/0247195 A1 1 1/2006 Ray altering the developmental potential. Accordingly, provided 2008/0293143 A1* 11/2008 Lin et al. ....................... 435/456 herein are compositions, methods, and kits comprising Syn 2009/0092616 A1* 4/2009 Snyder et al. 424,139.1 2009/0158513 A1* 6/2009 Robles .............................. 4,294 thetic, modified RNAs for changing the phenotype of a cellor 2009,0180996 A1 7/2009 Beyhan et al. cells. These methods, compositions, and kits comprising Syn 2009/0203141 A1* 8, 2009 Lin et al. ....................... 435/456 thetic, modified RNAs can be used either to express a desired 2009/0286852 A1 11/2009 Kariko et al. protein in a cell or tissue, or to change the differentiated 2010/0196889 A1* 8, 2010 Bankaitis-Davis et al. ....... 435/6 2010/0279.404 A1 11/2010 Yamanaka et al. phenotype of a cell to that of another, desired cell type. 2011/0065103 A1 3/2011 Sahin et al. 2011/0143397 A1 6/2011 Kariko et al. 8 Claims, 45 Drawing Sheets 2011/O14343.6 A1 6, 2011 Dahl et al. (21 of 45 Drawing Sheet(s) Filed in Color) US 8,883,506 B2 Page 2 (56) References Cited Papapetrou et al., Proc. Natl. Acad. Sci USA, 106(31): 12759-12764 (2009). "Stoichiometric and temporal requirements of Oct. 4, Sox2. 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"Virus free induction of sequences and modifications that determine RIG-IRNA binding and pluripotency and Subsequent excision of reprogramming factors.” signaling activities.” Kariko and Weissman, Curr. Opin. Drug Discov. Devel., 10:523-532 Van Den Bosch et al., J. Immunother, 29(5):512-523 (2006). “Simul (2007). “Naturally occurring nucleoside modifications suppress the taneous activation of viral antigen-specific memory CD4+ and CD8+ immunostimulatory activity of RNA: implication for therapeutic T-cells using mRNA-electroporated CD40-activated autologous RNA development.” B-cells. Kariko et al., Immunity, 23:165-175 (2005). "Suppression of RNA Van Tendeloo et al., Blood, 98(1):49-56 (2001). “Highly efficient recognition by toll-like receptors: the impact of nucleoside modifi gene delivery by mRNA electroporation in human hematopoietic cation and the evolutionary origin of RNA.” cells: Superiority to lipofection and passive pulsing of mRNA and to Kariko et al., Mol. 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