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(12) Patent Application Publication (10) Pub. No.: US 2012/025804.6 A1 Mutzke (43) Pub US 20120258046A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/025804.6 A1 Mutzke (43) Pub. Date: Oct. 11, 2012 (54) MANNOSE-CONTAINING SOLUTION FOR C7H 2L/02 (2006.01) LYOPHILIZATION, TRANSFECTION AND/OR CI2N 15/63 (2006.01) NECTION OF NUCLECACDS A61R 49/00 (2006.01) (76) Inventor: Thorsten Mutzke, Reutlingen (DE) (52) U.S. Cl. ....... 424/9.1: 435/.440; 514/44 R: 514/44 A: 536/23.1:536/24.5:536/24.3: 536/24.33; (21) Appl. No.: 131509,564 424/184.1 (22) PCT Filed: Nov. 8, 2010 (57) ABSTRACT (86). PCT No.: PCT/EP2010/006788 The present invention is directed to (the use of) a solution containing at least one nucleic acid (sequence) and free man S371 (c)(1), nose for lyophilization, transfection and/or injection, particu (2), (4) Date: May 11, 2012 larly of RNA and mRNA. The inventive solution exhibits a positive effect on Stabilization of the nucleic acid (sequence) (30) Foreign Application Priority Data during lyophilization and storage but also leads to a consid erable increase of the transfection efficiency of a nucleic acid. Dec. 9, 2009 (EP) ................... PCTAEP2009/OO8804 It thus also increases in vivo expression of a protein encoded by Such a nucleic acid upon increased transfection rate. The Publication Classification present invention is furthermore directed to a method of lyo (51) Int. Cl. philization using the mannose-containing solution, to phar A6 IK3I/7088 (2006.01) maceutical compositions, vaccines, kits, first and second A6 IK3I/73 (2006.01) medical uses applying such a mannose-containing Solution A6IP37/04 (2006.01) and/or a nucleic acid (sequence) lyophilized or resuspended C7H 2L/04 (2006.01) with Such a solution. Patent Application Publication Oct. 11, 2012 Sheet 1 of 6 US 2012/O25804.6 A1 : % & & O *** H-I Patent Application Publication Oct. 11, 2012 Sheet 2 of 6 US 2012/O25804.6 A1 sælduues6u?u?equod?uluue?o.id/VNDHuuuuou,VNDHuuJoAq??6??uI z?un61 o/o Aufseu le. Patent Application Publication Oct. 11, 2012 Sheet 3 of 6 US 2012/O25804.6 A1 £?un61-I —00L |-09 %. A feue Patent Application Publication US 2012/O25804.6 A1 #7?un61-I 000Z US 2012/025804.6 A1 Oct. 11, 2012 MANNOSE-CONTAINING SOLUTION FOR generated autologous APCs that are re-administred to LYOPHILIZATION, TRANSFECTION AND/OR patients (see e.g. Boczkowski, D., S. K. Nair, et al. (1996). NECTION OF NUCLECACDS “Dendritic cells pulsed with RNA are potent antigen-present ing cells in vitro and in vivo. J Exp Med 184(2): 465-72; CROSS REFERENCE TO RELATED Boczkowski, et al., 1996, supra), and the direct injection of APPLICATIONS naked RNA (see Hoerrr et al., 2000, supra). Despite all 0001. This application represents the U.S. National Stage progress achieved regarding gene delivery it is very important Application of International Application No. PCT/EP2010/ to improve further transfection efficiency to make nucleic 006788, filed Nov. 8, 2010, which claims priority to Interna acids especially RNA applicable for all imaginable therapeu tional Application No. PCT/EP2009/008804, filed Dec. 9, tic purposes. 2009, all of which are incorporated herein by reference in 0005. Application of RNA thus represents a favored tool in their entirety for all purposes. modern molecular medicine. It also exhibits some Superior properties over DNA cell transfection. As generally known, FIELD OF THE INVENTION transfection of DNA molecules may lead to serious problems. 0002 The present invention is directed to (the use of) a E.g. application of DNA molecules bears the risk that the Solution containing at least one nucleic acid (sequence) and DNA integrates into the host genome. Integration of foreign free mannose for lyophilization, transfection and/or injection, DNA into the host genome can have an influence on expres particularly of RNA and mRNA. The inventive solution sion of the host genes and possibly triggers expression of an exhibits a positive effect on stabilization of the nucleic acid oncogene or destruction of a tumor Suppressor gene. Further (sequence) during lyophilization and storage but also leads to more, a gene—and therefore the gene product which is a considerable increase of the transfection efficiency of a essential to the host may also be inactivated by integration of nucleic acid. It thus also increases in Vivo expression of a the foreign DNA into the coding region of this gene. There protein encoded by Such a nucleic acid upon increased trans may be a particular danger if integration of the DNA takes fection rate. The present invention is furthermore directed to place into a gene which is involved in regulation of cell a method of lyophilization using the mannose-containing growth. Nevertheless, DNA still represents an important tool, Solution, to pharmaceutical compositions, vaccines, kits, first even though some risks are associated with the application of and second medical uses applying Such a mannose-contain DNA. These risks do not occur if RNA, particularly mRNA, ing Solution and/or a nucleic acid (sequence) lyophilized or is used instead of DNA. An advantage of using RNA rather resuspended with Such a solution. than DNA is that no virus-derived promoter element has to be administered in vivo and no integration into the genome may BACKGROUND OF THE INVENTION occur. Furthermore, the RNA has not to overcome the barrier 0003. In gene therapy and many other therapeutically rel to the nucleus. However, a main disadvantage resulting from evant biochemical and biotechnological applications the use the use of RNA is due to its huge instability. Even though it is of nucleic acids for therapeutic and diagnostic purposes is of understood that DNA, e.g., naked DNA, introduced into a major importance. As an example, rapid progress has patient circulatory system is typically not stable and therefore occurred in recent years in the field of gene therapy and may have little chance of affecting most disease processes promising results have been achieved. Nucleic acids are (see e.g. Poxon et al., Pharmaceutical development and Tech therefore regarded as important tools for gene therapy and nology, 5(1), 115-122 (2000)) the problem of stability is even prophylactic and therapeutic vaccination against infectious more evident in the case of RNA. As generally known, the and malignant diseases. physico chemical stability of RNAs in solution is extremely 0004 Nucleic acids, both DNA and RNA, have been used low. RNA is very susceptible to hydrolysis by ubiquitous widely in gene therapy, either in naked or in complexed form. ribonucleases and is typically completely degraded already In this context, the application of nucleic acids and particu after a few hours or days in solution. This even occurs in the larly of RNA for therapeutic vaccination is revised perma absence of RNases, e.g. when stored a few hours or days in nently. On the one hand, nucleic acids and particularly RNA Solution at room temperature. or mRNA molecules can be optimized for a more efficient 0006 To avoid such degradation the RNA is typically transcription rate. The 5' Cap structure, the untranslated and stored at -20°C. or even -80° C. and RNAse free conditions translated regions are typically modified to stabilize the mol to prevent a prior degradation of the RNA. This method, ecule or to change its characteristics to enhance its translation however, does not prevent a loss of function effectively and properties (see e.g. Pascolo, S. (2008), Handb Exp Pharmacol additionally is very cost-intensive for shipping when these (183): 221-35). Further, different formulations of nucleic temperatures have to be guaranteed. One further method for acids and particularly of mRNA molecules or different deliv stabilization comprises lyophilization or freeze-drying of the ery routes are investigated to achieve improved expression RNA. Lyophilization is a worldwide known and recognized levels. To mention are the encapsulation into cationic lipo method in the art to enhance storage stability of temperature Somes or cationic polymers (see e.g. Hoerr, I., R. Obst, et al. sensitive biomolecules, such as nucleic acids. During lyo (2000), Eur J. Immunol 30(1): 1-7: Hess, P. R. D. Bocz philization, typically water is removed from a frozen sample kowski, et al. (2006), Cancer Immunol Immunother 55(6): containing nucleic acids via Sublimation. The process of lyo 672-83: Scheel, B., R. Teufel, et al. (2005), Eur J. Immunol philization is usually characterized by a primary and a sec 35(5): 1557-66), the needleless delivery of gold particles ondary drying step. During the primary drying step, free, i.e. coated by mRNA using a gene gun (see e.g. Qiu, P. P. Ziegel unbound, water Surrounding the nucleic acid (sequence) and hoffer, et al. (1996). “Gene gun delivery of mRNA in situ optionally further components, escapes from the solution. results in efficient transgene expression and genetic immuni Subsequent thereto water being bound on a molecular basis zation. Gene Ther 3(3): 262-8), the transfection of in vitro by the nucleic acids may be removed in a secondary drying US 2012/025804.6 A1 Oct. 11, 2012 step by adding thermal energy. In both cases the hydration Allison, et al. (2001), J Pharm Sci 90(10): 1445-55; and sphere around the nucleic acids is lost. Allison, S. D. and T. J. Anchordoquy (2000), J Pharm Sci 0007. During lyophilization the sample containing nucleic 89(5): 682–91). Lyoprotective properties are particularly acids is initially cooled below the freezing point of the solu described for Sucrose, glucose, and trehalose. They allow to tion and accordingly of the water contained therein. As a restore at least in part the transfection efficiency which is result, the water freezes.
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