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Spondence Address: A63L/7088 (2006.01) MUETING, RAASCH & GEBHARDT, P.A

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Spondence Address: A63L/7088 (2006.01) MUETING, RAASCH & GEBHARDT, P.A US 20080064647A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0064647 A1 Guo et al. (43) Pub. Date: Mar. 13, 2008 (54) PRNACHIMERA (60) Provisional application No. 60/433,697, filed on Dec. 16, 2002. (76) Inventors: Peixuan Guo, Mason, OH (US); Stephen M. Hoeprich, Canton, s (US); Dan Shu, Mason, OH Publication Classification (US) (51) Int. Cl. Correspondence Address: A63L/7088 (2006.01) MUETING, RAASCH & GEBHARDT, P.A. A6IP3L/00 (2006.01) P.O. BOX 581415 A6IP35/00 (2006.01) MINNEAPOLIS, MN 55458 C7H 2L/02 (2006.01) C07K I4/00 (2006.01) (21) Appl. No.: 10/539,241 CI2N 5/00 (2006.01) CI2N 7/00 (2006.01) (22) PCT Filed: Dec. 16, 2003 (86). PCT No.: PCT/USO3/399.50 (52) U.S. Cl. ....... 514/44; 435/235.1: 435/375; 530/350; 536/23.1 S 371 (c)(1), (2), (4) Date: Sep. 5, 2007 (57) ABSTRACT Related U.S. Application Data A polyvalent multimeric complex formed from a plurality of (63) which is a continuation-in-part of application No. circularly permuted chimeric pRNA molecules, each carry 10/373,612, filed on Feb. 24, 2003. ing a stabilized biologically active moiety. loop arm 1 SP arm2 Ribozyne. - > Ss EyeIndS to max- target RNA target RNA 11 Ribozyme Ribozyme s cleaves -o- dissociates from re- target RNA inactive RNA Patent Application Publication Mar. 13, 2008 Sheet 1 of 30 US 2008/0064647 A1 loop s Ribozyme --> S. Eyeinds to arm 1-sl-arm 2 target RNA - - - target RNA 11 Ribozyme s E. E. -o- s dissociates from re- target RNA inactive RNA fig. 1 Patent Application Publication Mar. 13, 2008 Sheet 3 of 30 US 2008/0064647 A1 CCA Bulge C t CA 5'JCAAUGGA-cG-GUACUUUGAUG 3 AGUUICAGCCGUGAA AACGUAC CAUAC-ACCC Region l UUUbifurcation bulge DNA packaging domain Region risis"-------------- Procapsid binding domain .9Fig.2b Patent Application Publication Mar. 13, 2008 Sheet 5 of 30 US 2008/0064647 A1 Patent Application Publication Mar. 13, 2008 Sheet 6 of 30 US 2008/0064647 A1 S () Sp S. s 'S cy Patent Application Publication Mar. 13, 2008 Sheet 7 of 30 US 2008/0064647 A1 fig. 5b Patent Application Publication Mar. 13, 2008 Sheet 8 of 30 US 2008/0064647 A1 Target RNA chimeric pRNA Target RNA bound to chimeric prNA 11 Target RNA cleaved by chimeric prNA Inactive RNA dissociates from chimeric pRNA - 2) O fig. 6a Patent Application Publication Mar. 13, 2008 Sheet 9 of 30 US 2008/0064647 A1 C Z D O E NQ () DS O s A-fO (9 SO E is E E is 5 5- 8-5 3 5 --0 Patent Application Publication Mar. 13, 2008 Sheet 10 of 30 US 2008/0064647 A1 5' UCAAGGOA-CG-GUACU us UUGUCAUG20 t GUAUGUGGGU - G CUGAU to All I All-Ahli lllllllll-ll. 3' U AA Agu-UCAGCCGUGAA OAccount &AC-AccC- GACUgO Patent Application Publication Mar. 13, 2008 Sheet 11 of 30 US 2008/0064647 A1 s g d Mar. 13, 2008 Sheet 12 of 30 US 2008/0064647 A1 aujosopuauoj Patent Application Publication Mar. 13, 2008 Sheet 14 of 30 US 2008/0064647 A1 Name of RNA Sequence of 3 3'overhang Structure overhang base number Eco-prNA AAGCC GAA UU (SEQID NO:19) 10 bases 3' overhang 10 bases XbHi-pRNA AAGCCGAAUUCC 59 bases AGCACACUGGCG GCCGUUACUAGU GGAUCCGAGCUC y GGUACCAAGCU 3' overhang 59 bases SEOD NO:20 174-pRNA CCUUUUACAUGC 54 bases GACACAGACGAA GCGCUAAAACGU GGGAUUCUGUG UCGUUUU (SEQID NO:21) 3' overhang 50 bases Di-RNA UCAAUGGUACGGESGXG 12012 bases CAUGUGUAUGUU GGGGAUUAAACC CUGAUUGAGUUC 3' overhang 120 bases AGCCCACAUACU UUGUUGAUUGGU UGUCAAUCAUGG CAAAAGUGCACG CUACUUUGAUAA (SEQ ID NO:22) fig. 10 Patent Application Publication Mar. 13, 2008 Sheet 15 of 30 US 2008/0064647 A1 fig. 11 a Small loop inserted Loop GGAATGG.T CCT GGAATGG......TTGCT A pRNA Coding Sea. pRNA Coding S'-end ses in p 6 --> -- p5 3'-end P8 -o- -- pla Reverse primers -- P2S se- P27 PCR -- P28G st-P37 -- PO7 S' y y PCR DNA Fragment Loop 3. in Yitro transcription CpRNA Transcripts p&A A s 7 20 is 38 s S5 a GGAAGGuA-cG-GUAcuuGUCAUG/ 5....S. GUAu...’, Ugg YGA's i? A. Allll ill lil ill cut-checo, O ecif AUAC-Acce- GACUC 08 16 9, 95 t-Gy' 49 A.Y. 78 U-A Ge. UG - 82 .9Fig.11b Large loop inserted Loop GGAATGG......TTCCT TAAACCGA GGAATGG - a - TGCTAA pRNA Coding Seq CTCACIATA 5'-end pRNA Coding Sea. p 6 -e- -- p5 PB -- -- p 17 Reverse primers --- P2S --- P27 PCR -- P286 --P37 Pud40-a- -- P39 P9s -e- -- P94 Forward primers P95 -e- --P9 -- PO7 PCR DNA Fragment loop in vitro transcripticn cpRNA Transcripts 4.44 ACUAu, u/ s 17Mc, 20 V8 u 38V 2.40 laS. 1. ^ Shi-Yi *Yes:i; stay; ; ; ; s; ; s ; ; G sauna ill-ill.i.e.,A” A -aa- M co-fA uAlic-acce-fictud 7 108 100 g 9S SR, 49 greA.Y. 78 -A G - 82 G Patent Application Publication Mar. 13, 2008 Sheet 16 of 30 US 2008/0064647 A1 Vy[] V[] mnVOnDOÐOnOnvnÐOnVOnDnmnnovno-oo-vmbo ir P to O PPP O D9)[][]VO T <C < O D CD P –OOov-OvnvöOV[1000VVVV0000OOOVOQºnnovo C)V|O .8VO Patent Application Publication Mar. 13, 2008 Sheet 17 of 30 US 2008/0064647 A1 R Z U 7 AAGCAGGG A cU. GUCCUA G G G A U fig. 13a Patent Application Publication Mar. 13, 2008 Sheet 18 of 30 US 2008/0064647 A1 N. o N pRNA.Rz 168 bases - G) U7 snRNA 94 bases - e. Cleavage product 69 bases -> RZ 47 bases --> Cleavage product25 bases - is fig. 13b Patent Application Publication Mar. 13, 2008 Sheet 19 of 30 US 2008/0064647 A1 s S o % 188mer prinA-RzA --> 137mer polyA signal 2Onef control -se 67me? and 7me? cleavage products 66rner RZA -e 63mer -> . Patent Application Publication Mar. 13, 2008 Sheet 20 of 30 US 2008/0064647 A1 1840uuoud (oalau?)awo|NO 0GI Patent Application Publication Mar. 13, 2008 Sheet 21 of 30 US 2008/0064647 A1 HBV Transcripts as 3.5Kb 2.112.4Kb Patent Application Publication US 2008/0064647 A1 Patent Application Publication Mar. 13, 2008 Sheet 23 of 30 US 2008/0064647 A1 s cy Patent Application Publication Mar. 13, 2008 Sheet 24 of 30 US 2008/0064647 A1 (229 Virion Capsid with 5-fold symmetry pRNA e hexarner DNA 2 -1 translociting D clona in D d O 1. Patent Application Publication Mar. 13, 2008 Sheet 25 of 30 US 2008/0064647 A1 Table A Two Interlocking prAs (l-a') + (A-i") (Compensatory A pair) Predete Hekater (miss one link) (Unpaired loop) + (C-a') (compensatory Predicted Hexanner fig. 20 Patent Application Publication Mar. 13, 2008 Sheet 26 of 30 US 2008/0064647 A1 MOCk HAd-AE1 E3 HAd-EphrinA 1-Sc HAd-EphrinA1-FC sa Patent Application Publication Mar. 13, 2008 Sheet 27 of 30 US 2008/0064647 A1 Patent Application Publication Mar. 13, 2008 Sheet 28 of 30 US 2008/0064647 A1 i 2 5 Patent Application Publication Mar. 13, 2008 Sheet 29 of 30 US 2008/0064647 A1 1 2 3 4 5 6 7 8 9 O Patent Application Publication Mar. 13, 2008 Sheet 30 of 30 US 2008/0064647 A1 FL5.12A --IL CD via O a y D & OO ON US 2008/0064647 A1 Mar. 13, 2008 PRNA CHMERA tremendous. The availability of a stabilized ribozyme that is resistant to degradation and is correctly folded such that it remains active in an intracellular environment would pave 0001. This application is a U.S. National Stage Patent the way for the development of many important medical Application of International Patent Application No. PCT/US therapies. 2003/039950, filed 16 Dec. 2003; which claims the benefit of U.S. provisional patent application Ser. No. 60/433,697. SUMMARY OF THE INVENTION filed Dec. 16, 2002, and is a continuation-in-part patent application of U.S. patent application Ser. No. 10/373,612, 0007. The invention provides a circularly permuted chi filed Feb. 24, 2003, which is a continuation in part appli meric pRNA molecule carrying a stabilized, properly folded, cation of PCT/US01/26333, filed Aug. 23, 2001, which in biologically active moiety. The pRNA chimera is formed turn claims the benefit of U.S. provisional patent application from a circularly permuted pRNA region, and a spacer Ser. No. 60/227,393, filed Aug. 23, 2000, each of which region that includes the biologically active moiety. The patent applications is incorporated herein by reference in its biologically active moiety is not limited to any chemical entirety. structure but is preferably an RNA, such as a ribozyme, siRNA (small, interfering RNA), an RNA aptamer or an STATEMENT OF GOVERNMENT RIGHTS antisense RNA. The spacer region is covalently linked at its 5' and 3' ends to the pRNA region. Optionally, the spacer 0002 This invention was made with government support region includes first and second nucleotide strings inter under grants from the National Institutes of Health (Grant posed between the biologically active moiety and the pRNA No. GM59944 and Grant No. GM48159) and the National region. Science Foundation (Grant No. MCB-9723923). The gov 0008. The invention circularly permuted chimeric pRNA ernment has certain rights in this invention. of the invention can be monomeric or multimeric. When multimeric, the circularly permuted pRNA is preferably a BACKGROUND dimer, a trimer or a hexamer, allowing the multimeric 0003. A ribozyme is an RNA molecule capable of cleav complex to be polyvalent. In a polyvalent multimeric com ing a target RNA molecule, or carrying out other catalytic plex, the multiple biologically active moieties may be the and enzymatic functions.
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