CA2178729A1 - Compounds and methods for site-directed mutations in eukaryotic cells - Google Patents

Compounds and methods for site-directed mutations in eukaryotic cells

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Publication number
CA2178729A1
CA2178729A1 CA002178729A CA2178729A CA2178729A1 CA 2178729 A1 CA2178729 A1 CA 2178729A1 CA 002178729 A CA002178729 A CA 002178729A CA 2178729 A CA2178729 A CA 2178729A CA 2178729 A1 CA2178729 A1 CA 2178729A1
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duplex
nucleic acid
region
chimeric
hybrid
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French (fr)
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Eric B. Kmiec
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Thomas Jefferson University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/80—Vectors or expression systems specially adapted for eukaryotic hosts for fungi
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
    • C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)

Abstract

The present invention concerns a polynucleotide having both ribonucleotides and deoxyribonucleotides in a first strand and solely deoxyribonucleotides in a second strand wherein the strands are Watson-Crick paired and are linked by an oligonucleotide so that the polynucleotide has at most a single 3' and a single 5' end. These ends can be ligated so that the polynucleotide is a single continuous circular polymer. The polynucleotide can be used to induce specific alterations in targeted genes.

Description

Wo 9S11S972 217 8 7 2 9 PCTIUS94/i4181 JUr~L~S AND METHODS FOR SITE-DIRECTED MUTATIONS
IN EUKARYOTIC CELLS
The present application i5 a Continuation-in-Part of 5 patent application Serial No. 08/164,303, filed De ' 9, 1993, which is hereby incvL~v-,ted by refGrence in its entirety .
1. FIELD OF THE lNV~
The present invention ~ the f ield of molecular genetics. Particularly it co1-ceL-13 nucleic acid __r.ds and methods Or their use to introduce specif ic genetic alterations into living cultured eukaryotic cells. More particularly it c - o~ l rl substantially Watson-Crick paired, 15 duplex nucleic acids wherein a portion of one strand of the duplex comprises a 2 '-O or 2 '-OMe ribose containing nucleotides and the I~ ;nrlor comprise deoxyribose nucleotides .
2. BAc~ uNL1 TO THE lNv~ l(JN
2 . l . CHI!5ERIC AND/OR HYBRID DUPLEX NUCLEIC AcIDs The field of the invention cvnceL..s nucleic acids.
25 Nucleic acids are heteropolymers, i.e., polymers of non-identical subunits, which are linked by oriented rhn~Fhnrl; oRter bonds or their derivatives, into polymers .
Duplex nucleic acids are nucleic acids wherein each base of a first strand of the duplex curLG~ùllds to a base of a second 30 strand of the duplex according to the scheme in which uracil or thymine and adenine CV~G- ,~UIId and cytosine and guanine CULL-__~V~ld. Ant~-parallel duplex strands having these CUL~ V~ r r~r7 are said to be Watson-Crick paired. Duplex nucleic acids can be of two major types, rihnn~ lo;c acids 35 and deoxyribonucleic acids . Each ri hnnl-r l o~tide has an equivalent deoxyribonucleotide, e.g., adenosine and devAy~ n~;no, cytidine and deoxycytidine, guanosine and WO 95/lS972 21~ 8 7 ~ 9 PCr/lJS91/14181 ~
deoxyguanosine, uridine and thy~idine. As used in th~ field, a nucleic acid in which both ri hrmllrleotides and deoxyribonucleotides are press!nt in the s~me strand is termed a mixed or chimeric (hereinafter "chimeric") nucleic acid. A
5 duplex nucleic acid in which deoxyri h~n~rleotides and rihnn~r1~Otide8 COLLe:D~ with each other is termed a hybrid-duplex. When two strzmds form a region of duplex nucleic Acid for less than all of their bases, the resultant molecule is termad a heteroduplex.
lo Most often, the two fitr~nds of a duplex nucleic ~cid are not covalently bonded but are associated only by Watson-Crick pairing. However, the two strandE~ of a duplex can be linked by an oli~onllrleotide to form a single polymer. The linking olignnllrl ~otide is not Watson-Crick paired. The heteroduplex 15 in which the f ir8t and second strands are portions of a single polymer i8 termed a "hairpin duplex" or a "stem and loop" structure. The former term will be used hereinafter.
As used herein chimerism i8 a ~L~ L ~Y of a nucleic acid polymer and hybridism i8 a ~L~ L Ly of a duplex. For 20 example, an mRNA and its template form a hybrid duplex though neither is chimeric, while, for example, the chimeric oct A m I r 1 eotides 5 ' d ( TTTT ) -r ( CCCC ) 3 ' and 5 ' r ( GGGG ) -d ( AAAA ) 3 ' will form a Wat~;on-CriCk duplex with each other but the resultant duplex is not a hybrid-duplex. A duplex nucleic5 acid which is not a hybrid-duplex is termed hereinafter a lex". Unless specifically noted otherwise, a homo-duplex nucleic acid refers only to a ~eu~y~ cleotide containing duplex. Lastly, ncte that while those in the field refer to the formation of a Wat60n-Crick duplex as 30 "hybridiz~tion, " even where there is no hybrid-duplex nucleic acids .
Those intere6ted in the 8tudy the structure of chimeric and/or hybrid duplex nucleic acids by X-ray diffraction and 2-~ inn:~ l NMR have synth~ e~ chimeric nucleic acids and 35 hybrid duplex nucleic ~cids for use in their studies. See, e.g., S~lazar, M., et al., 1994, J.Mol.8iol. 241:440-55 and Egli, N., et ~l., 1993, ~orh~ try 32: 3221-37 (two WO gS/15972 ~17 8 7 2 9 PCT/US94ll4l8l .ded chimeric hybrid duplex of the form r3d~-d~0); Ban, C., et al., 1994, J.Mol.Biol. 236:275-85 (self ~ ~tary chimeric hybrid duplex of the form d5rld4); Chou, S.H., 1991, BiorhPm~ctry 30:5248-57 (self-complementing and non-self-5 _ 1~ ~ lng chimeric hybrid duplexes of the form d4r4d4) .The compl ~y strands of these duplex nucleic acids were not covalently ~ound to each other; they were associated only by Watson-Crick pairing.
A second group of scientists who have synth~ci7~d 10 chimeric nucleic acids are those interested in the study and use of ribozymes , i . e ., RNA molecules that are either self-cleaving or cleave other RNAs. Perreault, J.P., et al., 1990, Nature 344:565; Taylor, N.R., et al., 1992, Nucleic Acids Research 20:4559-65; Shimaya, T., 1993, Nucleic Acids 15 Regearch 21:2605. These researches have found that chimeric ribozymes are active and are more resistant to nuclease digestion than RNA ribozymes. Chimeric ribozymes are self-compl y, i . e., the Watson-Crick paired strands are covalently linked. The _ ~~ synthesized during the ZO studies of chimeric ribozymes di~fer from the a~ no~ed hybrid-duplex molecules, that were synth~C; 7~7d used for ~u~ur~l studies, in that chimeric ribozymes do not contain stable hybrid-duplexes. Thus, a chimeric ribozyme having DNA
binding arms binds to its substrate and f orms a hybrid 25 duplex. Yang, J.H., et al., 1990, Biorh~mi~try 29:11156-60.
See also, Sawata, S., et al., 1993, Nucleic Acids ReseaL~I.
21:5656-60; Hendry, P., et al., 1992, Nucleic Acids Research 20:5737-41 Shimayama, T., 1993, Nucleic Acids Research 21:2605. The ribozyme catalyzes the cleavage of the RNA
30 substrate and the hybrid-duplex is thus dissolved.
2 . 2 . SITE--DID~ECTED GENETIC AT-TFD~rTnN IN EUXARYOTIC CELLS
Those skilled in the art of ~ c~ r biology r~co~n ~ 70 35 that on Lle~u~ll- OrrlCiCInC it is desired not merely to ~ L~duce a new polynucleic acid s~ e, i.e, a new gene, into a targeted eukaryotic cell, but rather to alter a Wo 9~15972 2 1 7 8 7 2 9 ~ PCrlUSg~1114181 O
,~, . ;. ~
defined, pre-existing gene in the targeted cell. The targeted cell can be used in culture or it can be used to COll_~r UUL a trAn~ ni n animal.
A wide variety of technL,ues have been developed to 5 iI~u-luce DNA into cultured eukaryotic cells. These t~Ahn;qu~ii include calcium phosph_te precipitation and DEAE-dextran mediated endocytosig, ele-;L~uyu-AAtion, 11L~~
mediated fusion ~md ~r AF~ L~ ~n with replication ; ~ nt viruses. HoweVer, while such techniques can quite often 10 introduce fl~n~ tinnAl genes into the eukaryotic cell, these techniques do not readily accomplish an alteration (mutation) in a specific eYisting gene. After il~LL.aduL;Lion the exogenous DNA is isolated at a random position in the cell ' s genome by illegitimate L~ inAtion~ rather than at a specific lS position by homologous r~ Ation.
To date there is no generally satisfactory scheme for illLLuducing a site-directed or site-specific genetic alterntion ( ~a~J_ rcis:) in a higher eukaryote, i.e, in l iAn or avian cells. Although homologous L~ ` ;nAtiOn 20 can be obtained in higher eukaryotic cells by i..L udu~ Lion of very long (> 1 kb) nucleic acids, these techniques reguire the application of elaborate selection techniyues because the rate of illegitimate L- - ~ ;nAtion in higher eukaryotes greatly exceeds that of homologous r~- inAtion. Thomas, 25 K.R. & rAre~A~ h;, N.R., 1987, Cell 52:503. See, also, V~1An~ c, V. & SmithieS 0., 1991, Mol. Cell. Biol. 11:4389 (comparison h- Ioqouc ~ nAtion of linearized and supercoiled rlAA~~-lc in eukaryotic cells).
One a~LOa- l~ to achieving a E~ inAAntly site-directed ~0 mutagenesis has been the il.Llo~ Li~'n of single stranded oli~udeu~y..ucleotides directly into the cell. This techniques has been a -~-arully employed in the yeast SacchAromyces cerevisi~e, in which homologous l~ lnAtion is signif icantly more active than it is in hiyher eukaryotes .
35 Il~c~ L~ll, R.P., et al., 1988, Proc.Natl.Acad.Sci. 85:524-28; Yamamoto, T., et al., 1992, Yeast 8:935-48. However, to date there have been no reports of the ~ 6r~l wo 95/15972 217 ~ 7 2 9 PCT/US94/14181 transformation of mammalian or avian cells by single stranded ol i~om-rlPntide8.
A relatinnRhir between the ~LueLure of the target DNA
and the rate of homologous recombination in 1 i An can be 5 inf erred by studies that show that regions of alternating purine and pyrimidine bases, i.e., [d(TG)30-d(AC)30], display an entranced rate of 1~ inAtion. These effects were .,~ed in studies of non-replicating plAr"id~ in cultured 1 iAn cells. Wahls~ W.P., et al., 1990, Mol.
10 Cell . Biol . 10: 785-93 . These experiments were not extended to show r~_ i nAtion between an ~ J ~ ~ nucleic acid and the genome of the cell.
Attempts have been made to use RecA, a protein that promotes homologous LS_ ' inAtion in the bacteria, E. coli, lS to promote homologous recombination in eukaryotic cells.
However, these attempts have not been clearly s~lccDscful.
For eYample U.S.Pat No. 4,950,599 to W, Bertling dicclo~es a very low rate of site-directed mutation and no ~nhAnr L in the rate of hl -loqo~c recombination by use of RecA in 20 eukaryotic cells. Patent publications W0 93/22443 to D.
Zarling and E. Sena, and publication 94/04032 to D.C.
GLue.l~LL and R. R~no~ nn both purport to correct a genetic defect in a cultured cell line related to cystic fibrosis.
These publications d i crlo~e primarily experimental data that 2S d LL~Le the principle rather than data concerning 1~ of operative methods. Thus, to il~L-Jdul_e polynucleotide/RecA complexes access to the nucleus, Zarling and GLU~ LL employ cells that were membranc p. -hil~
although such cells are incapable of further growth.
~0 Moreover, even when RecA-promoted homologous recombination was asserted to have taken place in intact cells, these publications provide no quantitative estimates of its frequency. Thus, the use of prokaryotic recA has not been convincingly shown to result in a rate homologous 35 ~ inAtion in any viable eukaryotic cell ci~nifirAntly grêater than the spontaneous rate of homologous I ~ '- i nAtion .

WO 95115972 217 ~ ~ 2 ~ PCTIUS94/14~81 0
3 . ST~IARY OF TdE INVENTION
The present inventioi C~ LI-3 single covalently linked dupleY oligc~n~ lentides that are homologous with a gene of 5 intere6t having both deoxyr;'~nl~ l-?otides and r~h~n~ le~tides. In order to eT-fect a genetlc change there are within the region of homology one or more non-c~ rl;ng (hereinafter "heterologous" or "mutator") base pairs. The norm~l, constitutive r~ lAr ~oce~es o homologous r~_ ';nAnts cause the mutator nucleotides to be inserted into the targeted genomic site. The duplex ol igr~n~ leotides of the invention (hereinafter "chimeric vectors") can be used to alter specifically a gene of interest by introducing into the gene the heterologous base lS pairs. The heterologous base pairs can be base pairs different from the gene of interest, or base pairs in addition to those present in the gene of interest (an insertion), or, lastly, the heterologous base pairs can be the absence of base-pairs found in the gene of interest (a 20 delef i on) . The present invention is based, in part, on the discovery that the ; nr~l l7cinn Of a region of between about 15 and 50 base pairs of hybrid-duplex nucleic acid in the vector causes a greatly increased rate of alteration of the gene of interest. T-'hen the region of the heterologous base pairs is 2S between 1 and 50 base pairs, the heterologous base pairs can be present in the vectors of the invention as either a homo-or a hybrid-duplex. ~'hen the heterologous base pairs are greater than 50 base pairs in length it is preferred that they be present as a homo-duplex.
The vector can be i.. LLo-luced into the target cell by any method known to allow for the intror'~lr tir-n of nucleic acids into eukaryotic cells. Without limitation as to theory, the chimeric vector is believed to be engaged by the rt _ 'inAtion/repair Tlr ~' -n; ~ ~ of the target cell and to 35 direct a the alteration of the target gene by gene conversion or by homologous, :c 'in ~tion.

wo 95/1S972 217 ~ 7 2 ~ PCT/US94/14181
4. BRIEF DESCRIPTION OF THE FIGURES
Figure l shows the schematic ~ se~,Lation of two chimeric vectors. The following, are particularly labeled: l, a first strand; 2, a second strand; 3, a heterologous region;
S 4, A homologous region; 5, a linker; 6, a lig~tion site.
Symbol Key for Figure l RNII /WV\
~0 D~ ¦ ¦ h ~'U, ~) I I I I unpalr~d Figure lA is a ligated chimeric vector in the R-D-R
form .
2 Figure 18 is a hairpin chimeric vector in the R-D-R form having a single 3 ' and 5 ' end.
5. nrATATT.T~n ~k5c.~l~1l0N OF THE INVENTION

5.1. D~;S~,K1~ JN OF THE CHIMERIC VECTOKS OF ~HE lhv~n~lLJN
The present invention _r~ ~ - Ae duplex nucleic acids that contain both deoxyribose and ribose containing bases.
Thus they contain region6 of both DNA and RNA and are termed therefore termed "chimeric vectors. " The 2 ' -O of the r~ h~ Aleotides of the chimeric vector can be methylated.
Any rhGD~ i PRter can be substituted by a rl~r~.k. .. ~l h i ~ i ARter or L¦1y1~hA~D~h~ l i ester.
The chimeric vectors of the invention are a single nucleic acid polymer. Accordingly, the chimeric vectors of the invention must contain at least one region of between at WO 95/1~972 217 8 7 2 9 PCT/US94114181 ~
least l base and more usually 3 or 4 ba_es that are not Watson-Crick paired. These unpaired regions serve as linkers between the two strands of Watson-Crick paired bases. In contrast to other chimeric nucleoti~les that have been 5 synthesized having regions of unpi~ired nucleotides chimeric vectors have no enzymatic activity i . e., they do not catalyze rh~-m;rAl r~-Art1rnc or themselves undergo rh~micAl reaction in the absence of an biological energy source such as ATP.
The bases of the linkers in the preferred ~ L are 10 deoxyr;hrn1~rleotides. A chimeric vector having two linkers can be constructed 80 that the 3 ' and 5 ' ends of the polymer are Watson-Crick paired to adjacent nucleotides of the , l Lary strand. They can then be readily ligated 80 that the chimeric vector forms a single continuous circular lS nucleic acid polymer.
Substantially all the r. in;n~ bases of the chimeric vector are Watson-Crick paired. As used herein the statement that bases are Watson-Crick paired or that they form a duplex nucleic acid is to be understood to mean that 20 under the proper conditions of t~ UL.~ and salt they are capable of forming base pairs or a duplex nucleic acid. It is to be understood that under some conditions of low salt and/or elevated t~ _ ALu~c the Watson-Crick base pairs may cease to be th~L 'y ~ i cA l l y stable such that the duplex 25 nucleic acid melts-out or d~..aLu~ c:8. It is also to be understood that a one or two base pair mismatch does not effect the operability of the invention.
The chimeric vectors of the present invention are ;nt~n~d for the purpose of specifically introducing 30 alterations ta mutation) into a target gene. The genetic site of the alteration is det~rm; nc.d by selecting a portion of the chimeric vector to have the same ~ re as (to be homologous with) the sequence of the target site, hereinafter termed a ~ -log~1~c region. The area of differences between S5 the ~e~ ,e of the chimeric vector and the target gene are termed the heterologous region. Note that the chimeric vector is heterologous to the target gene, but is not a heteroduplex in this region of the vector. According to the preferred . 'i- t of the invention there are two homologous regions in each chimeric vector f lanking the interposed heterologous region, all three regions being 5 present in a sin~-le continuous duplex nucleic acid. Further according to the invention each homologous region contains a portion of hybrid-dupleX nucleic acid. The portion of each hybrid-duplex can be at leat 4 base pairs and preferably is 8 base pairs and more preferably about 20 to 30 base pairs.
10 The function of the chimeric vector i8 not effected by a dinucleotide base pair Or ~ lu~lex within a region of hybrid duplex, placed to allow ligation of the 3 ' and 5 ' ends to each other. The total length of the two homologous regions can be at least 20 base pairs and preferably is ~5 between 40 and 60 base pairs.
According to the invention, a region of h' .lu~lex nucleic acid can be A i cpos~d between the hybrid-duplex - lo~o~c regions of the vector . The interposed homo-duplex can contain the heterologous region. When the heterologous 20 region is less than about 50 base pairs and preferably less than about 20 base pairs, the p..eL.~ce of a interposed homo-duplex region is optional. When the heterologous region exceeds about 20 base pairs, an interposed }- du~lex that cnrt~inc the heterologous region is preferred.
5 . 2 . C. ..~ ,N OF THE CE~IHERIC VECTORS OF TE~E INVENTION
The chimeric vectors of the invention can be synth~-ci 7ed by any method. The chimeric vectors can most readily be 30 synthesized by modification of the techniques used in the ~olid phase synthesis of DNA . Reviewed Caruthers , M. H ., 1985, Science 230:281-85; Itakura, R., et al., 1984, Ann.Rev.Biochem. 53:523-56. Modifications to permit the synthesis of RNA and of chimeric nucleic acids are disclosed 35 in Scaringe, S.A., et al., 1990, Nucleic Acids Research 18:5433-41; Usman, N., et al., 1992, Nucleic Acids Research z0:6695-99; and Swiderski, P.M., et al., 1994, Anal. Biochem _ g _ WO 9S/15972 2 1 ~ ~ 7 2 9 PCT/IJ594/14181 Z16:83-88, which are hereby in~ t,Led by reference in their entirety. Recent advances concerning the synthesis of chimeric nucleic acids are rQviewed in Usman, N. & Cedt:
R., 1992, Trends Bioch. Sci. 17:334-9.
S Chimeric vectors having a ~ ~ du~lex region interposed between two hybrid-duplex regions can be u ~ulDLL~ ~ed using semisynthetic to~hniql~oc:. Two synthetic chimeric polynucleic aaids having a hairpin conformation are to be constructed.
The free 5 ' and 3 ' ends of the two chimeric nucleic acids are 10 c~ ,u- Led with an overlap ~ eled ends compl- ~IL~ to the overl~p o~ two different restriction enzyme digest ~r~duuLs. A h~ - duylex region is provided having the compl- y restriction enzyme digested ends. The addition of a re6triction enzyme sites to the ends of a cloned DNA
15 fr L can be accomplished by te~hniql~o~ well understood by those skilled in the art, e.g., without limitation, PCR
amplification with extended primers or the blunt end ligation o~ linker~ containing the restriction site. The two chimeric nucleotides and the h~ - du~lex region can be ligated by 20 conventional enzymatic techniques. The product, having chimeric ol ignm~n~eotides ligated at both ends can be separated from the incompletely reacted substrates by eleu~Lu~lo~esis in 6% polyacrylamide gel in Tris Borate EDTA
buffer under n~-l dell~LuLing conditions. The linear capped 25 molecules are constrained and are eleuLL-~l-,c,Lesed more slowly under these conditions.
Chimeric vectors containing only naturally occurring nucleotides can be used for the present invention. The chimeric vectors having regions of hybrid-duplex of about 20 30 rihnml~ l~ntides are found, in vitro, to be resistant to RNAse H. Resistance to enzymatic degradation can be obtained by the repl ~ L of the ri hnr~ll-~l eotides with 2 ' -0 methylated rihnml~ otides. Additionally or alternatively the rllngrhn~ ter bonds of the nucleic acid can be replaced by 35 rl~n~rhn~o~hio~ ters. Shimayama, T. et al., 1993, Nucleic Acids RCL~7-LUI~ 21:2605. Arabinose containing nucleotides can also be used. As used herein the term nucleic acid is ~ wo gs/lsgn 2 ~ 7 8 7 2 9 PCT~USg4/l4l~
intended to ~ ~. nucleic ~cidD having these modif ications .
5 . 3 . THE USE OF THE CHIMERIC V~CTORS OF THE INVENTION
The chimeric vectors of the present invention can be used to a mutation in a specif ic location in the genome of a target cell. The specific location of the target location is defined by its nucleic D~ e hereinafter the target 10 se~l~-nre. According to the invention a chimeric vector is cvl,DL~ ucLed wherein the homology regions are identical to the target s~qu~nre, except for the presence of some regions of hybrid-duplex. The change to be introduced i5 encoded by the heterologous region. The change may be change in one or more 15 bases of the sPq~nre or the addition o~ one or more bases.
When the change in the target sequence is the addition of less than about 20 bases the invention may be practiced using one or two regions of hybrid duplex. When the change in the target ~oqu~nre is the addition of more than about 50 bases 20 it is preferred that the heterologous region be c~nt~ined within a h~ ~u~lex region.
The practice of the invention requires that the chimeric vector be il~LLu-luced into the nucleus of the target cell.
Any method which causes such il.LLu~u. Lion can be used. Such 25 methods include elevLLvL~v-c-tion~ DEAE-dextran, Ca PO4 precipitation, liposome mediated fusion (Ll~Or~scLlN), and direct injection. ElecLLu~uL~tion is particularly suitable.
In one : ~ - ' i L of the invention the chimeric vector can be used to cul,DLlu~L L~An~ ;C animals. The chimeric 30 vector can be introduced into the prnnllrl F~llc of a ovum by direct injection, according to the method described Brinster, R.L. et al., 1989, PROC.NATL.ACAD.SCI 86:7087; see also U.S.
Patent No. 4,873,191 to T.E. Wagner and P.C. Hoppe, which are hereby in-uL~uL~ted by reference in their entirety.
~5 Alternatively, the chimeric vector can be introduced into an embryonic stem cell, chimeric animals can be ~Lvduv~d by ~yL~.ILion of the embryonic stem cell with normal blastocyst Wo 95/1~972 217 8 7 2 9 PCT/USs~/14181 ~
cells, and LL , ; n animals can be rec~v~L d as of f spring of the chimeric animals , according to the method of ~r~ h i, M.R., 1989, Science 244: 1288, which i5 hereby inC~L~LC~ted by reference in its entirety.
Using ~le~ L~ltion, as~ many as l cell per lO, 000 treated cells can be speci~ically mutated at the target se~ ce thereinDfter "transformed"). The practice of the invention, thus, includes the Use of a method to select the transformed cells from among the larger number of unmutated 10 cells. In one ~ 'i- ~ the transformation of the cells confers a growth advantage. Non-limiting eYamples of such growth advantages include drug-resistance, alterations in growth regulation, and alterations in the capacity to utilize metabolites . In an alternative '~ ~ ' i - L the method of 15 selection can be negative selection whereby the transformed cells are rendered in~ ~r~hle of growth under the selecting conditions and the non-transformed cells are removed by JO.~ L 1:: to conditions which selectively destroy proliferating cells.
Alternatively, the transformed cells may have an altered cell-surface antigenic ~ y~e that can be detected by immunofluu..:s. ~=... e and selection can be performed by a Flu~Jl.asce... e Activated Cell Sorter.
When the method of introducing the chimeric vector into 25 the cell is direct injection, as for example when cv~ L~ ing ~LA~ in animals by pronuclear injection, the rate of transformation can be greater than l per lO,000 cells. The need for selection is thereby rnn~ ably reduced.
SO Typically useful amount5 of a chimeric vector are between lO and lOoO ng of chimeric vector per million cultured cells to be transformed by ele.;~L~,~L,L~tion.

Wo 95/15972 217 8 7 ~ 9 PCT/US94/14181
6. EXAMPLES
6 . l . 15xu~1pl- l: In V~vo Activity in Ustilngo rungu~, Wild-type rl6tilago has a functioning ura-3 gene whose 5 product is part of the uracil biosynthetic pathway. When wild-type Ustil~so iB grown on 5 '-fluororotic acid (SFOA) -media the cells die due to incv-~-,-~Lion of the acid into the pathway. If the ura-3 gene is mutated BO that ura-3 mRNA is not ~Lvduced, the cells survive on the 5FOA media.
The sequence of the t~ O~t~rlt~llC ura-3 gene is known in the art. In one set of experiments, base 358 of the setln~ t e was changed from a thy-midine to an adenine which mutation results in a lyDrùll~ Lional protein.
A chimeric vector was syntht~ci ~ocl as follows:
15 Vector for mutation at base 358: (358 RNA Vector) 5 ' TGCCGATrG~r~ ...vulJ~,CCGA~' ' :rAAA'rTT 3 ' (SEQ ID: l) The 358 vector adopts hairpin conformations. Underlined 20 bases indicate ribonucleic acid residues. The bolded letter indicates the mutator (heterolOgous region)~ The it~lit i~scl "T" ' 8 indicate the unpaired bases .
A vector having the same 5eq--t~nt'e but containing no ribonucleic acids was also c-,~lDL.u- Led for use as a control.
25 In the vector thymidine was substituted for uracil.
The control vector for mutation at base 358: (DNA 358 Vector) 5 ' TGCCGATCGGrA~ JC~-7ATrGGr~AA'rTT 3 ' (SEQ ID:
2) also adopts a hairpin conformation. Again, the bolded residue is the mutator.
An ~n vivo trans~ormation experiment was carried out in which U. maydis cells (107) were made into protoplasts with a ~c-,ve ,y of 106 cells in a 50 ILl transformation buffer solution following methods well known in the art and transfected with different amounts of the chimeric vectors or 3S ~ 3 ~ (DNA alone) vector were mixed with the protoplasts at 37 C. The cells were then plated on selective media and the number of surviving colonies (transformants) WO 95~15972 217 8 7 2 9 PCT/US94/14181 ~
were counted. The results ~re presented in tabular form below: ~
Tr~n~f-ction V-ctor - 358 Numb~Or of A-lount Typ- 8ur~r~ ving 5(I~g~ C~ol~
o . l DNA o 0.1 chimeric 13 o . 2 5 DNA
0 . 25 chimeric 49 0 . 75 DNA 12 0.75 chimeric 131 1. 0 DNA 19 lS l. o chimeric 573 These data show that transfection of cells with the RNA
358 Vector increases the survival of the cells at a much greater rate than transfection with the C~LL-7l~ 1;n~ DNA
vector .

6 . 2 . 15~c~mpl- 2: Thn Tr-T~of - i~ of NI~ 3T3 C~lla.
NIH 3T3 cells are human cells that have a benign (controlled) growth characterigtic8. MA1~ 11Ant t~ G--LLolled) growth characteristics are ~..fe~Lcd by the single point mutation in the c ~ ~oy-~ ~ 8-ras that replaces Glyl2 by Thr. Thus, the mutation G ITI2 leads to a readily selectable alteration in the growth characteristics.
Iel~aL. _ly, E., et al., 1982, Nature 300:762; Sukumar S., et al., 1983, Nature 306:658.
~ himeric vectors were cL.IlsLL.~.;Led to direct the G--TI2 mutation having the following sequence:
5 '--~-A5AC~ 7 ~jG G,~ A~ A~ ,GG~`~,C'~ ,G~ ,G~ --3 ' (SEQ ID: 3) The se~ re is presented in the conventional single letter code with the additional features the i~NA (underlined), unpaired bases are it~llcized, and the mutator base is bolC.

~ WO 95/15972 217 ~ ~ 2 9 PCTIUS94/14181 Note that after circularization the chimeric vector i5 divided into two ~.ul,D~nLially complementary 6trands by the two trithymidinyl 6eqU~n~DC and that all the ribose containing nucleotides are present in only one of the two S strands.
Two forms of the chimeric vector were synth~s; 7sd using 2 '-OMe ribose bases having respectively one (nR") and two ( "R-D-R" ) regions of hybrid duplex f lanking f our deoxyribose residues. The R-D-R form is shown above, SEQ ID:
l0 3, the R form is identical eYcept that bases 6-9 ("CGAC") were deoxynucleotides. Note that the 5 ' and 3 ' termini are deoxynucleotides. The allows the chimeric vectors to be circularized after synthesis by use of the same DNA ligase ~.uc~ s as are commonly employed in recombinant DNA.
lS After ligation, the circularization chimeric vector6 were isolated from the substrate by two iterations of ~ tive ele- L.v~1....i3is in D600 gel (AT Biochem, Malvern, PA).
Control vectors were: l) the same sequence lacking hybrid-duplex (data shown, ~'h~ - d~.~lex"); 2) the unpaired 20 DNA (data shown "sDNA") having the sequence 5'-G~Cr~'ArC'~''GGC`G~AC'~'A~-3' (SEQ ID 4); 3) the chimeric vector having no heterologous region and hence no mutator nucleotide (data not shown).
The experiment was c~n~lcted by transforming NIH 3T3 25 cells (l x 106 cells) using an ele~ L~ .tion pl~ce.luLe.
After ele~:L~ Lion, the cells were plated at a seeding density of 4 x 103 cells/cm2 and allowed to grow for 14 days in culture. Tr~nsformants were v;~ l;7ed by staining foci-forming cells with crystal violet. As a positive control, 30 the plasmid pT24 that encodes the T12 form of H ras was employed. Thi6 control was used to determine the level of illegitimate 1~ ' inAtion in the transfected NIH 3T3 cells.
The experiment was repeated f ive times and a summary of the results are presented in tabular form below. In addition to 35 the results pressnted below the control experiments that used a chimeric vector having no mutator codon showed no transformed ~oci of NIH 3T3 cells.

wo ssllssn 217 8 7 2 9 PCT/US94/14181 ~
Vector T~e l~mt Tr~ f ected Trans~ormants (per 10~ cells) ~er 106 cells ( 14 days~
pT24 (positive lO~g 57 Scontrol ) sDNA l~g 2 sDNA lO~g 13 lu~lex l/ g o h~ - .Iul lex lOILg 2 10chimeric 50ng R-D-R R

chimeric 200ng 55 43 chimeric l~Lg 139 103 These results show that the chimeric vectors introduced a spec~fi~- mutation by homologou6 recombination ~;o as to transform 1 i ~n cells. The rate of transformation in this experiment was greater than the rate of transformation by illegitimate r~_ ' in~tion that was observed by 20 transfection with pT24 positive control vector, which crnt~inPr~ an entire mutated ~-ras gene. Thus, by use of chimeric vectors a rate of homologous recombination in a n cell was achieved that was greater than the rate of illegitimate recombination.

~5 WO 9S/15972 217 8 ~ 2 g PCT/US94/14181 æEQUENOE LISTINC
( 1 ) GENERAL lh~
(i) APPLICANT~ I~miec, Erlc li) TITLE OF INVENTION Compoundl~ nd MethodY for sLt- Dlr-ct~d Nut~tlon~ ln lSuk~ryotlc C~
(lll) NUM8ER OF SEQUENOES: 4 lv) ~rw .~rl ADDRESS
(A) ADDRESSEE Pennie ~ Edmonds (B) STREET: 1155 AvPnue of th~ Alrler~c--8 (c) CITY: New York ( D ) STATE: NY
15 (F) ZIP 10036--2711 (v) CONPUTER READABLE FORM:
(A) NEDIUH TYPE Floppy dL-k (B) COMPilTER IBN PC - ~ hl ~
(C) OPERATING SYSTEM: PC--DOS/NS--DOS
20 (D) SOFTW~~E: PAtentIn Rele~e ~1 0, Vers$on J1 25 (vi) CURRENT APPLIQTION DATA:
(A) APPLIQTION NUMBER~ US
( B ) F ILI NG DATE
(C) CLASSIE'IQTION

(vill) ATTORNEY/AGENT INFORMATION:
(A) NAME Frl~bel, Thom~s E
(B) P~''T~TP-TI U NUMBER 29,258 (C) ~r /DOCEET NUN~3ER 7991--009 ~ (i8C) T~T- --Tt~N lNrl lUa:
(A) TELEP80NE (212) 790-9090 (B) TELEFAX (212) 869--8864/9741 (2) lrrl ~ FOR SEQ ID NO:1:

(1) SEQUENCE rP~-~T~oT~TT~c (A) LENGTII 37 b~se p~lr-WO 95/~5972 2 1 7 8 7 2 '~ PCT/US94114181 ~
lB) TYPEs nuclQLc acLd (C) ,~ t 801~ ~ 1. ' Y
(D~ TOPOLO&Y: lLnear (LL) MOLECULE TYPE: DNA/PNA

( Lx ) Fll A=
(A) NA~5E/~ Y: _ (B) LOCATION: l9. .32 (D) OTHER 1l~.. lUn: /lab--l-- a 10 /not-l-- "RNA~
(xL) SEQUENCE Ur.~-:n~ n: SEQ ID NO:l:
15 CAACTTTTGU uarr.~Trr~ CAAATTT 37 (2) lrlr~ ~ FOR SEQ ID NO:2:
( L ) SEQUENCE rT'' "' ~
(A) LENGTH: 37 bal~e paLr-(B) TYPE: nucl~Lc ~cLd 20 (C) 6~ elf 1~ .ry (D) TOPOLOGY: lLn-ar (LL) MOLECULE TYPE: DNA

(xl) SEQUENOE ~;u;n~ n: SEQ ID NO:2:
CA~CTTTTGT TGCCGATCGG CAAATTT 37 12) 11._. ~ FOR SEQ ID NO:3:

( L ) SEQ~ENOE r (A) LENGTH: 53 ba~l3 paLr~
(B) TYPE: nuclelc Acld (C) : lltllf _ 1 T y ( D ) TOPOLOGY: 1 Ln--Ar lL) MOLECULE TYPE: DNA/RNA

WO 95/15972 217 8 ~ 2 9 PCT/US94/14181 ( Lx ) FEATU~E:
( A ) NAME /~EY
(B) LOCATION: 2..5 (D) =R lhr~ ~ : /l~b~ b - /not---- "RNA"
( ix ) FEATURE:
(A) NAME/I~EY
(B) LocATInN: 10. .21 (D) OTHER -T~'N: /l bel- d /note-- "RNA"

( lx ) FEATURE:
(A) NANE/l~EY: --(B) ~OCATION: 51..52 (D) OTHER lhr- --Tt~ bel-- f /notc= "RNA"
lS
(x$) SEQUENOE ~ rl~ Jn: SEQ ID NO:3:
r~r~.~cr.~~a ~ r---r~ ~C~ . GCC 53 20 (2) Lrlr~ ~ FOR SEQ ID NO:4:
( i ) SEQUENCE rl~ 7 (A) LENGTH: 23 b~e p~lir (B) TYPE: nucl~ic ~cid ( C ) ~ ~ ~ r (D) TOPOLOGY: lLnellr (Li) NOLECULE TYPE: DNA
(xL) SEQUENOE Lc,o~ lU.. : SEQ ID NO:4:
a~rr~-r~lrrG ~rr~ r~r~r CAC 23

Claims (17)

Claims:
1. A chimeric nucleic acid having at most one 3' end and one 5' end, which nucleic acid further comprises:
a. a region of contiguous unpaired bases disposed so that the unpaired region separates the nucleic acid into a first strand and a second strand;
b. a region of Watson-Crick paired nucleic acid of at least 15 base pairs in length, in which bases of the first strand correspond to bases of the second strand, and in which;
c . the first strand comprises a region of at least three contiguous nucleotides comprised of a 2 '-O or 2 ' -OMe ribose, which are Watson-Crick paired in a hybrid-duplex .
2. The nucleic acid of Claim 1 in which the second strand contains no nucleotides comprised of a 2'-O or 2'-OMe ribose .
3. The nucleic acid of Claim 2 in which the hybrid-duplex comprises at least 9 contiguous nucleotides comprised of a 2 '-O ribose flanked by nucleotides comprised of 2'-deoxyribose.
4 . The nucleic acid of Claim 2 in which the first strand comprises two regions of contiguous nucleotides comprised of a 2'-O or 2'-OMe ribose that form two regions of hybrid-duplex, each hybrid-duplex region having at least 4 base pairs of length, and an interposed region of at least 1 base pair of homo-duplex disposed between the hybrid duplex regions .
5 . The nucleic acid of Claim 2 in which the first strand comprises two regions of nucleotides comprised of a 2'-O or 2'-OMe ribose that form two regions of hybrid-duplex, each hybrid-duplex region having at least 8 base pairs of length, and an interposed region of at least 4 base pairs of homo-duplex disposed between the hybrid duplex regions.
6. The nucleic acid of Claim 5 in which the interposed region of homo-duplex is consists of between 4 and 50 2'-deoxyribose base pairs.
7. The nucleic acid of Claim 5 in which the interposed region of home-duplex is consists of between 30 and 1,000 2'-deoxyribose base pairs.
8. The nucleic acid of Claim 2 in which the 5' and 3' ends are ligated.
9. The nucleic acid of Claim 5 in which the 5' and 3' ends are ligated.
10. The nucleic acid of Claim 6 in which the 5' and 3' ends are ligated.
11. The nucleic acid of Claim 7 in which the 5' and 3' ends are ligated.
12. A method of introducing a predetermined alteration in a target sequence of the genome of a cell, having a nucleus, which comprises the steps of:
a. providing a chimeric vector having two regions homologous with a target sequence and a heterologous region, disposed there between, encoding the alteration;
b. maintaining the chimeric vector within the nucleus of the cell such that the chimeric vector and the target sequence genetically recombine.
13. The method of claim 12 wherein the nucleus is an pronucleus of an ova and the introduction is by direct injection.
14. The method of claim 12 wherein the nucleus is a nucleus of an embryonic stem cell and the introduction is by direct injection.
15. A method of obtaining a cell population having altered characteristics which comprises the steps of:
a. providing a chimeric vector having two regions homologous with a target sequence and a heterologous region, disposed there between, encoding the alteration;
b. maintaining the chimeric vector within the nucleus of the cell whereby the chimeric vector and the target sequence recombine and the cell is transformed; and c. selecting the transformed cells .
16. The method of claim 15 wherein the cell is a yeast or fungus.
17. The method of claim 15 wherein the cell is a yeast or fungus.
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