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(12) Patent Application Publication (10) Pub. No.: US 2014/0227300 A1 Chin Et Al US 201402273 00A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0227300 A1 Chin et al. (43) Pub. Date: Aug. 14, 2014 (54) INHIBITION OF INNATE IMMUNE CI2N 5/077 (2006.01) RESPONSE A613 L/7II (2006.01) (75) Inventors: CynthiaO Chin,- O Madison, WI (US); (52) CPCU.S. Cl............. CI2N5/0634 (2013.01); A61K3I/7II Anthony D. Person, Madison, WI (US); (2013.01); C12N5/0696 (2013.01): CI2N Gary A. Dahl, Madison, WI (US) 5/0658 (2013.01) (73) Assignee. CELLSCRIPT, LLC, Madison, WI USPC ......... 424/184.1; 435/375; 435/372:435/377 (US) (57) ABSTRACT (21) Appl. No.: 14/129,703 The present invention provides methods, kits, and composi (22) PCT Filed: Jun. 27, 2012 tions for reducing an innate immune system response in a human or animal cell, tissue or organism. One embodiment (86). PCT No.: PCT/US2O12/044418 comprises: introducing an Agent mRNA comprising in vitro S371 (c)(1), synthesized mRNA encoding one or more proteins that affect (2), (4) Date: Apr. 2, 2014 the induction, activity or response of an innate immune response pathway; whereby, the innate immune response in Related U.S. Application Data the cell, tissue or organism is reduced compared to the innate (60) Provisional application No. 61/501,420, filed on Jun. immune response in the absence of the Agent mRNA. Other 27, 2011. embodiments are methods, compositions and kits for using an s Agent mRNA for treating a disease or medical condition in a Publication Classification human oranimal that exhibits symptoms of an elevated innate immune system, or for reducing an innate immune response (51) Int. Cl. that is induced in a human or animal cell, tissue or organism CI2N 5/078 (2006.01) by a Foreign Substance that is administered to the cell, tissue CI2N 5/074 (2006.01) or organism. Patent Application Publication Aug. 14, 2014 Sheet 1 of 11 US 2014/022.7300 A1 FIG. 1 --I !, Patent Application Publication Aug. 14, 2014 Sheet 3 of 11 US 2014/022.7300 A1 FIG. 3 ?,= ----|:: Patent Application Publication Aug. 14, 2014 Sheet 4 of 11 US 2014/022.7300 A1 FIG. 4 Patent Application Publication Aug. 14, 2014 Sheet 5 of 11 US 2014/022.7300 A1 FIGS 3OOOO 25OOO 2OOOO 15OOO 1OOOO 5OOO - Patent Application Publication Aug. 14, 2014 Sheet 6 of 11 US 2014/022.7300 A1 FIG. 6 30 25 20 15 Untreated Mock ALKP ALKP Transfected EGFP Untreated Mock ALKP ALKP + Transfected EGFP Patent Application Publication Aug. 14, 2014 Sheet 7 of 11 US 2014/022.7300 A1 FIG 7 8000 5000 4000 3000 OOO - Untreated Mock LIN28 dsRNA LIN28 dsRNA - LIN28 dsRNA Transfected (cMYC mRNA) (E3L mRNA) US 2014/022.7300 A1 Aug. 14, 2014 INHIBITION OF INNATE IMMUNE Type III IFNs consist of 3 IFNs and signal through IFNLR1 RESPONSE and IL-10R2. At present, not much is known regarding type III IFNs other than that they are known to regulate an antiviral FIELD OF THE INVENTION response and may be the ancestral type IIFNs (Levraud et al., 2007). 0001. The present invention provides methods, kits, and compositions for reducing an innate immune system response 0004 Elevated type IIFN levels have been shown to play in a human or animal cell, tissue or organism by introducing major roles in the disease states in autoimmune disorders into the cell, tissue or organism an Agent mRNA comprising Such as psoriasis and systemic lupus erythematosus (SLE) or consisting of mRNA encoding one or more proteins that (Hua et al., 2006; Kirou et al., 2005; Nestle et al., 2005). affect the induction, activity and/or response of an innate Neutralization of type I IFNs or type I IFN receptors with immune response pathway; whereby, the innate immune anti-interferon pathway-specific antibodies have been shown response in the cell, tissue or organism is reduced compared to reduce psoriasis and SLE disease progression (Nestle et al., to the innate immune response in the absence of introducing 2005; Yao et al., 2009). the Agent mRNA. Other embodiments are compositions or 0005 Viral infections initiate an innate immune response kits comprising an Agent mRNA for treating a disease or in infected cells resulting in a cascade of intracellular events, medical condition in a human or animal that exhibits symp ultimately resulting in the secretion of interferons. Triggering toms of an elevated innate immune system, or for reducing an the innate immune response can result in apoptosis of the cell innate immune response that is induced in a human or animal or inhibition or repression of protein synthesis. Immunorec cell, tissue or organism by a Foreign Substance that is admin ognition of viruses is dependent on detection of viral nucleic istered to the cell, tissue or organism for a biological, medical, acids by PPRs, including TLRs. TLR3 activates an innate agricultural or research purpose. immune response by recognizing and binding to virally-de rived dsRNA (Alexopoulou et al., 2001; Wang et al., 2004). BACKGROUND TLR9 is activated by DNA containing unmethylated CpG motifs, found in viral and bacterial DNA (Hemmi et al., 0002 The innate immune systems of humans and animals 2000). Single-stranded RNAs (ssRNA) and small interfering comprise a number of different mechanisms by which cells in RNA (siRNAs) are recognized by TLR7 and TLR8 (Diebold these organisms recognize and respond to a variety of differ et al., 2004; Heil et al., 2004; Hemmi et al., 2002: Judge and ent pathogen-associated molecular patterns (PAMPS) on for MacLachlan, 2008). TLR4 activates an innate immune eign Substances or damage-associated (or danger-associated) response by recognizing and binding to LPS of Gram-nega molecular patterns due to components released due to dam tive bacteria. Innate immune responses induced by different aged cells or stress signals from damaged cells (DAMPS). foreign Substances activating different TLRs can be medi Pattern recognition receptor (PRR) proteins, including mem ated, at least in part, through common signaling pathways. brane-bound toll-like receptors (TLRs) and cytoplasmic For example, activation of both TLR3 and TLR4 trigger sig NOD-like receptors (NLRs), recognize a variety of different naling pathways that result in production of type I interferons ligands as foreign, damaged, or non-self (e.g., pathogen-as (IFNs). Sociated or damage-associated) and activate one or more 0006 Vaccinia virus (VV), a cytoplasmic DNA virus in innate immune response pathways that function to defend the the poxvirus family, encodes a set of intracellular proteins or organism. In some cases, the innate immune response path soluble cytokine binding proteins that enhance virus viru way may result in damage or death of the cell after binding of lence. VV intracellular E3L protein, an inhibitor of interferon a ligand on a foreign substance to the PRR of the cell. For induction, binds to dsRNA and prevents the activation of the example, a type I interferon (IFN) response is induced upon IFN-induced protein kinase PKR (Chang et al., 1992). VV binding of double-stranded RNA (dsRNA) to toll-like recep intracellular K3L protein binds competitively to PKR and tor 3 (TLR3) or binding of a Gram-negative lipopolysaccha blocks the phosphorylation and inactivation of host eIF-2C. ride (LPS) to TLR4, and these IFN responses can inhibit (Beattie et al., 1991). VV also encodes a secreted IFNC/B protein translation in the cell and induce many other innate receptor that is encoded by the B18R gene (Colamonici et al., immune response pathways that result in damage to the cell, 1995; Symons et al., 1995). This B18R gene encodes a or, if Sustained over time (e.g., by repeated exposure to the secreted glycoprotein that binds to and inhibits the function of foreign substance comprising dsRNA or LPS over multiple type I interferons (IFNC/B), while not binding nor inhibiting days), result in death of the cell. type II interferons (IFNY) (Symons et al., 1995). Vaccinia 0003. The Interferon family of cytokines is one key com strains lacking functional B18R show much lower levels of ponent of the innate immune response to both bacterial and viral virulence demonstrating the importance of inhibiting viral infection. Interferons were discovered more than 50 type I interferons during viral infection (Colamonici et al., years ago as biological agents that inhibited the replication of 1995; Symons et al., 1995). influenza virus (Isaacs and Lindenmann, 1957). Interferons 0007. In vitro-transcribed mRNA made from SP6, T7 or are designated type I-III based on the receptor complex they T3 RNA polymerases have been shown to function in count signal through. Type I IFNs, which comprise 13 IFNC. Sub less studies when used for directinjection into Xenopus laevis types, IFNB, IFNK, IFNe, IFNo, IFNT and IFNö, engage the (frog) or Danio rerio (Zebrafish) ooyctes as well as for trans ubiquitously expressed IFNAR (IFNC. receptor) complex that fection into mammalian cells in culture. It is well established is composed of the IFNAR1 and IFNAR2 subunits. The func that in vitro transcription using T7 RNA polymerase can tions of Type I IFNs are well characterized and known to be result in the generation of some dsRNA in addition to the essential for mounting a robust anti-viral response (Muller et desired ssRNA (Cazenave and Uhlenbeck, 1994; Triana al., 1994). Type II IFNs consist of the single IFNY protein that Alonso et al., 1995). Introduction of viral dsRNA or the binds the IFNY receptor (IFNGR) complex. IFNY secretion synthetic dsRNA cohomopolymer polyinosinic-polycyti functions primarily to inhibit pathogens other than viruses. dylic acid (polyI:C) results in the activation of a TLR3-me US 2014/022.7300 A1 Aug. 14, 2014 diated innate immune response (Alexopoulou et al., 2001; tive inhibitor” means afragment, mutant, analog or variant of Schulz et al., 2005).
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