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Mat Kadi Tora Tutti O Al Ut Hit Hitta Atuh MAT KADI TORA TUTTI USO AL20180235194A1 UT HIT HITTA ATUH ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0235194 A1 Fahrenkrug et al. (43 ) Pub . Date : Aug . 23, 2018 ( 54 ) MULTIPLEX GENE EDITING Publication Classification (51 ) Int. Ci. ( 71 ) Applicant: Recombinetics , Inc ., Saint Paul, MN A01K 67/ 027 (2006 . 01 ) (US ) C12N 15 / 90 ( 2006 .01 ) (72 ) Inventors : Scott C . Fahrenkrug, Minneapolis , (52 ) U . S . CI. MN (US ) ; Daniel F . Carlson , CPC .. .. A01K 67 / 0276 (2013 . 01 ) ; C12N 15 / 907 Woodbury , MN (US ) ( 2013 .01 ) ; A01K 67 /0275 ( 2013 .01 ) ; A01K 2267/ 02 (2013 .01 ) ; AOIK 2217 / 15 (2013 .01 ) ; AOIK 2227 / 108 ( 2013 .01 ) ; AOIK 2217 /07 (21 ) Appl. No. : 15 /923 , 951 ( 2013 .01 ) ; A01K 2227/ 101 (2013 .01 ) ; AOIK ( 22 ) Filed : Mar. 16 , 2018 2217 /075 ( 2013 .01 ) (57 ) ABSTRACT Related U . S . Application Data Materials and methods for making multiplex gene edits in (62 ) Division of application No . 14 /698 ,561 , filed on Apr. cells and are presented . Further methods include animals 28 , 2015, now abandoned . and methods of making the same . Methods of making ( 60 ) Provisional application No . 61/ 985, 327, filed on Apr. chimeric animals are presented , as well as chimeric animals . 28 , 2014 . Specification includes a Sequence Listing . Patent Application Publication Aug . 23 , 2018 Sheet 1 of 13 US 2018 / 0235194 A1 GENERATION OF HOMOZYGOUS CATTLE EDITED AT ONE ALLELE USING SINGLE EDITS Edit allele , Raise FO to Mate FO enough times Raise F1s to Mate F1 siblings Clone cell , sexual maturity , to produce enough F1 sexualmaturity , to make Implant, Gestate 2 years generation carrying 2 years homozygous KO , 9 months , birth edited allele to mate 9 months of FO with each other Generation Primary Fibroblasts ? ? ? Time, years FIG . 1A GENERATION OF CATTLE GENETICALLY EDITED AT MULTIPLE ALLELES USING SINGLE EDITS AA ( AAAAA ( ( ( ( ) ó naAAAAA * * * 20 30 40 50 60A + + Time , years FIG . 1B Patent Application Publication Aug. 23 , 2018 Sheet 2 of 13 US 2018 / 0235194 A1 GENERATION OF HOMOZYGOUS CATTLE EDITED AT MULTIPLE ALLELES Edit allele , Clonel ImplantGestate 9 months , birth of FO generation Genetic editing at multiple alleles in Primary Fibroblasts or embryos Time, years FIG . 2 . Patent Application Publication Aug. 23 , 2018 Sheet 3 of 13 US 2018 / 0235194 A1 Z Rag2 NHEJ NIL2RG NHEJ Rag2 HDR b e L2Rg HDR n Day 3 Day 11 of om å 2222 o ZZZZZZZ 1 ,000 ng mRNA 1 , 000 ng mRNA RAG2 2 UM HDR template 2 UM HDR template IL2Rg mRNA ( ng ) 1, 000 2 ,000 1 ,000 2 ,000 IL2RG HDR (UM ) 0 .5 2 .0 | 4 .0 0. 5 | 2. 0 4 .0 0 .5 2 .0 40 . 0 .5 2. 0 4 .0 IL2RY IL2Ry n = 6 n = 7 6 % 14 - n - 6 RAG2 RAGŽ n = 41 n = 46 29 % 36 % n = 139 clones n = 128 clones Genotypes Genotypes IL2Rg - ly : 6 ( 4 % ) IL2Rg - ly : 7 ( 4 % ) RAG2 + / - : 26 ( 19 % ) RAG2 + / -: 38 (30 % ) RAG2 - /- 15 ( 11 % ) RAG2 - 1- 18 ( 6 % ) IL2Rg - y : RAG2 + / - : 9 ( 6 % ) IL2Rg - /y : RAG2 + / -: 3 ( 2 % ) IL2Rg - ly : RAG2 - 1- 5 ( 4 % ) IL2Rg - ly : RAG2 - 1- : 3 ( 2 % ) FIG . 3 Patent Application Publication Aug. 23 , 2018 Sheet 4 of 13 US 2018 / 0235194 A1 3 p53 NHEJ I APC NHEJ 0 p53 HDR b APC HDR • Day 3 Day 11 D Percent HDR/NHEJ p53 2000 ng TALEN MRNA ; 0 . 2 n Mol 2000 ng TALEN MRNA ; 0 . 2 nMol 053 2000 HDR Template HDR Template APC HDR 2 UM 2 UM APC mRNA ( ng) 1, 000 500 250 100 1 ,000 500500 250 100 APC APC 33 % 33 % p53 p53 39 % 39 % n = 45 n = 46 Colonies with 3 + HR Colonies with 3 + HR 1 : APCins/ ins ; p53ins/ ins 2 : APCins /ins : p53 + / ins 1 : APC + /ins ; p53ins /ins 1 : APCins/ ins ; p53+ /ins FIG . 4 Patent Application Publication Aug . 23, 2018 Sheet 5 of 13 US 2018 / 0235194 A1 8 2 uM each oligo 8 8 8 H 3 C o b 8 1 uM each oligo 8 5 3 m UI o RAG2 | IL2Rg | p53 APC LDLR TALEN MRNA (ng ) 1 , 000 2 ,000 2 ,000 1 , 000 2 , 000 O % NHEJ D3 % HDR D3 % HDR D10 FIG . 5 Patent Application Publication Aug . 23 , 2018 Sheet 6 of 13 US 2018 / 0235194 A1 p53 IL2Rg APC RAG2 LDLR Genes RFLP + TITILA edited (percent ) TM1 5 2 ( 3 ) SONOROCCO0000000 4 0 3143 ( 4 ) MINIT -NWA.2 12 ( 17 ) 1 24 ( 33 ) 1 + 41 (57 ) ARABA E 38 % 19 % 21 % 8 % 7 % n = 72 Het -RFLP + W Homo- RFLP + RFLP + w / additional indel * * Determined by gel analysis a - probability of genotype is 0 .001 percent. Binomial prediction for independent derivation of this genotype is K > 2 ; p < 2 .55 E - 7 or 0 . 000026 % . FIG . 6 Patent Application Publication Aug . 23 , 2018 Sheet 7 of 13 US 2018 / 0235194 A1 APC KISSR RAG2 LDLR EIF4G / IN TTTTTM TTTIIIII a Genes RFLP + 1 b edited (percent ) cono-ocmanhcocomxcrack TTTTT 5 0 4 5 ( 5 ) 3 7 (7 ) 23 (24 ) 29 (30 ) 1+ 63 (66 ) ho - Het- RFLP + RR8 Mrr WIL Homo- RFLP + 44 % 42 % 18 % 13 % 5 % RFLP + w / additional indel* n = 96 * Determined by gel analysis a - Probability of this genotype 0 .0000066 % ; K 21; p = 0 . 0006 or 0 .06 % . b . Line 5 ; probability of genotype 0 . 00073 ; K 2 1 ; p = 0 .067 or 6 . 7 % . FIG . 7 Patent Application Publication Aug . 23 , 2018 Sheet 8 of 13 US 2018 / 0235194 A1 APC DMD KissR LDLR RAG2 b Genes RFLP + TUTTI www Ooo edited (percent ) 4 ( 2 ) .UL 14 ( 7 ) 41 ( 21 ) 47 ( 24 ) 106 (55 ) VITITIT Z7272 LILOMETIME TA - D Het -RFLP + Homo- RFLP + RFLP + w / additional indel * TTD * Determined by gel analysis 23 % 26 % 27 % 13 % 7 % a - Top line probability of success . = 0 . 001 ( 0 . 1 % ) . K 21; p = 0 . 17 ; 17 % . b - Second line : probability of success 0 .00002 . K > 1 ; p = 0 .0019 ; or 0 . 19 % C - Fourth line : probability of success 0 . 0025 . K2 1 ; p = 0 . 38 ; or 38 percent. FIG . 8 Patent Application Publication Aug . 23 , 2018 Sheet 9 of 13 US 2018 / 0235194 A1 ADD TARGETED NUCLEASES TO INACTIVATE TARGET GENES OR CHANGE GENE ALLELES SOMATIC PERFORM LOW -PASSAGE LIVESTOCK CELLS CULTURE OF CELLS TEST COLONIES OF CELLS TO CHOOSE DESIRED KNOCKOUTS OR DESIRED ALLELES con CLONE CELL DEVELOP BLASTOCYST WITH HOST CELLS OF DONOR CELLS DESIRED GENOTYPE ADD DONOR CELLS TO HOST BLASTOCYST TO MAKE CHIMERA OF DONOR AND HOST CELLS FO GENERATION V F1 GENERATION 1 GENERATION AND PROGENY 1 SURROGATE ESTABLISHES 13 > WITHPROGENY DESIRED LINE AT FO STAGE 33 3 ? ? GENOTYPEE FIG . 9 Patent Application Publication Aug . 23, 2018 Sheet 10 of 13 US 2018 /0235194 A1 EMBRYO WITH FAILURE TO THRIVE PHENOTYPE & GENOTYPE CAUSED BY GENE KNOCKOUT DONOR CELLS WITH FUNCTIONALO o GENES TO RESCUE Poº EMBRYO WITH FTT GENOTYPE ( ) ene& NORMAL PHENOTYPE NORMAL PHENOTYPE FTT Ette Y PHENOTYPElirement FIG . 10 Patent Application Publication Aug . 23, 2018 Sheet 11 of 13 US 2018 /0235194 A1 DONOR CELLS DONOR WITH DESIRED BLASTOCYST GENETICS oO G -HOST HOST BLASTOCYST WITH INACTIVATION OF GENES REQUIRED TO FORM FUNCTIONAL GAMETES CHIMERA WITHOUT ITS OWN GENETIC GAMETES CHIMERIC ANIMAL PRODUCES PROGENY OF DONOR CELLS FIG . 11 Patent Application Publication Aug . 23, 2018 Sheet 12 of 13 US 2018 /0235194 A1 ctcttttcgcaggcacaggtctacgagctggagcgacgcttoTaaGcTTgcagcagcggtacctgtcggctcccgagcgtgaccagttggSEQIDNO:1 aaccctgtgtcgtttcccacccagtagatatgtttgatgactAqGcTtctcggaaggcagagagtgtgtcaactgeggggccatgtccacSEQIDNO:2 SEQIDNO:3 IITTITY OligoSequence FIG.12 TALENS TALENS IIIIIIIIIIIIIIIV tgeggttgctcccccgcctcgtccccg|TAAGCTTgactcctggtgcagcgccccggccagTTgactcctggtgcagcgccccggccagtgcggttgctcccccgcctcgtcc ???????????DNAbinding DNAbindingMITIM DNAbindingm NUNUNUNUNUN TALENS NKX2-5C GATA4 MESP1C Target NKX2-5 GATA4 MESP1 Nkx2-5 a) GATA4 Patent Application Publication Aug . 23, 2018 Sheet 13 of 13 US 2018 /0235194 A1 TALEN CRISPR EIF4GIP65 12. 5 2 . 5 % RFLP FIG . 13 US 2018 /0235194 A1 Aug. 23 , 2018 MULTIPLEX GENE EDITING and “ D ” ) for HDR at APC , p53 or both . Colonies with 3 or more HDR alleles are listed below . CROSS REFERENCE TO RELATED [0010 ) FIG . 5 Effect of Oligonucleotide HDR template APPLICATIONS concentration on Five - gene multiplex HDR efficiency . Indi cated amounts of TALEN mRNA directed to swine RAG2, [0001 ] This application is a Divisional of U . S . patent IL2Rg, p53 , APC and LDLR were co - transfected into pig application Ser. No . 14 /698 ,561 filed on Apr. 28 , 2015 ; fibroblasts along with 2 uM (panel a ) or 1 uM (panel b ) of which claims priority to U . S . Provisional Application No . each cognate HDR template . Percent NHEJ and HDR were 61 /985 , 327 , filed Apr. 28 , 2014 , each of which are incorpo measured by Surveyor and RFLP assay. rated herein by reference in their entirety . [0011 ] FIG . 6 is a five - gene multiplex data set that shows plots of experimental data for the effect of oligonucleotide TECHNICAL FIELD HDR template concentration on 5 - gene multiplex HDR [ 0002 ] The technical field relates to gene editing at mul efficiency . Indicated amounts of TALEN mRNA directed to tiple sites, multiple gene edits in vertebrate cells , and uses swine RAG2 , IL2Rg, p53 , APC and LDLR were co - trans thereof. fected into pig fibroblasts along with 2 uM (panel a ) or 1 uM (panel b ) of each cognate HDR template . Percent NHEJ and BACKGROUND HDR were measured by Surveyor and RFLP assay . Colony genotypes from 5 - gene multiplex HDR : Colony genotypes [0003 ] Genetic modifications to cells , and to animals made were evaluated by RFLP analysis . Panel a ) Each line rep from such cells , are useful for changing the expression of resents the genotype of one colony at each specified locus. genes. The field of genetic engineering is very active . Three genotypes could be identified ; those with the expected RFLP genotype of heterozygous or homozygous HDR as SUMMARY OF THE INVENTION well as those with an RFLP positive fragment, plus a second [0004 ] It would be very useful to make large vertebrate allele that has a visible shift in size indicative of an insertion animals that, in a single generation , have multiple changes or deletion ( indel ) allele .
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