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W O 2017/180669 a L 1 9 October 2017 (19.10.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2017/180669 A l 1 9 October 2017 (19.10.2017) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 15/90 (2006.01) C12N 15/09 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, C12N 15/87 (2006.01) C07H 21/04 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (21) International Application Number: KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, PCT/US20 17/027073 MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (22) International Filing Date: NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, 11 April 2017 ( 11.04.2017) RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (25) Filing Language: English ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 62/320,863 11 April 2016 ( 11.04.2016) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: APPLIED STEMCELL, INC. [US/US]; 521 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Cottonwood Dr., Milpitas, California 95035 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: KONG, Ling-jie; 1018 Gull Ave, Foster City, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, California 944404 (US). TSAI, Ruby Yanru; 5869 Capil- GW, KM, ML, MR, NE, SN, TD, TG). ano Dr., San Jose, California 95 138 (US). Published: (74) Agent: ZHU, James; Jun He Law Offices P.C., 2100 Geng Rd., Ste. 102, Palo Alto, California 94303 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, (54) Title: SITE-SPECIFIC INTEGRATION OF TRANSGENES f ► I — >- fc - 1 > -| o 00 I (57) Abstract: Provided is a method for knocking in a gene of interest to a cell. The genome of the cell contains a negative select - able marker, e.g., a thymidine kinase gene flanked by a pair of recombinase recognition sites (RRS), e.g., attP. The method involves o introducing into the cell a targeting construct that contains a gene of interest flanked by a second pair of RRS, e.g., attB. The target ing construct also contains in the vector backbone a negative selectable marker, e.g., thymidine kinase gene. When a recombinase re cognizing the RRS is expressed, the recombination events between the two pairs of RRS result in the site-specific integration of the gene of interest in the genome of the cell. Upon selection based on the negative selectable marker, the parental cells, cells with un- desired integration, e.g., random integration, or the integration of the vector backbone are removed. SITE-SPECIFIC INTEGRATION OF TRANSGENES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional patent application no. 62/320,863, filed April 11, 2016, the disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention generally relates to methods for integrating transgenes into a specific genomic locus in a cell. BACKGROUND [0003] Site-specific integration (i.e., knock-in) of a transgene into the chromosome of a mammalian cell is a technology that has broad applications in basic and applied biology. A typical process for site-specific integration involves the steps of 1) introducing a targeting vector containing a gene of interest into mammalian cells and 2) screening and selecting transfected cells with integration of the gene of interest at specific genomic locus. The efficiency of integration at a specific genomic locus is usually very low, and the screening and selection process is usually achieved by single cell cloning which is time consuming and labor intensive. In addition, the integration of the gene of interest together with the vector backbone DNA in the genome often leads to unwanted effects, such as the silencing of the gene of interest. Therefore, there is a continuing need to develop methods that can speed up the knock-in process and generate cells that do not contain the integration of the backbone DNA of the targeting vector. SUMMARY [0004] In one aspect, the present disclosure provides a method for inserting a transgene of interest into the genome of a cell. In one embodiment, the method comprises the step of introducing a targeting construct into a cell whose genome comprises a landing pad. The landing pad comprises sequentially (i) a first recombinase recognition site (RRS), (ii) a first negative selectable marker, and (iii) a second RRS. The targeting construct comprises (a) an exchange cassette and (b) a selectable cassette. The exchange cassette comprises sequentially (i) a third RRS, (ii) the transgene of interest, and (iii) a fourth RRS. The selectable cassette comprises a second negative selectable marker. The method further comprises the step of expressing a site-specific recombinase in the cell, wherein the site- specific recombinase recognizes at least the first and the third RRS. The cell is then maintained under a condition that facilitates recombination between the first and the third RRS, and between the second and the fourth RRS, wherein at least the recombination between the first and the third RRS is mediated by the site-specific recombinase. Cells with site-specific integration of the transgene are selected. [0005] In certain embodiments, the landing pad is located in the genome of the cell at a region of increased gene expression (RIDGE). Examples of the RIDGE include, without limitation, a Hippl 1 (HI 1) locus, a ROSA26 locus and a AAVS1 locus. [0006] In certain embodiments, the targeting construct can be liner or circular. [0007] In certain embodiments, the first negative selectable marker can be the same as the second negative selectable marker. In certain embodiments, the first and the second negative selectable marker can be different. In certain embodiments, the first or the second negative selectable marker is a thymidine kinase gene. [0008] In certain embodiments, the landing pad further comprises a positive selectable marker. In certain embodiments, the positive selectable marker is an aminoglycoside phosphotransferase gene (neomycin resistance gene), a puromycin-N-acetyl transferase (puromycin resistance gene) or a blasticidin S deaminase (blasticidin S resistance gene), or hygromycin B phosphotransferase gene (hygromycin resistance gene). [0009] In certain embodiments, the first RRS is the same as the second RRS. In certain embodiments, the first RRS is different from the second RRS. In certain embodiments, the third RRS is the same as the fourth RRS. In certain embodiments, the third RRS is different from the fourth RRS. In certain embodiments, each of the first, the second, the third and the fourth RRS is independently selected from the group consisting of attB, attP, FRT, loxP, mutants thereof and tandem repeats thereof. [0010] In certain embodiments, the site-specific recombinase is selected from the group consisting of Cre, Flp, the lambda integrase, gamma-delta resolvase, Tn3 resolvase, Sin resolvase, Gin invertase, Hin invertase, Tn5044 resolvase, IS607 transposase, Bxbl, wBeta, BL3, phiR4, A 118, TGI, MRU, phi370, SPBc, TP901-1, phiRV, FCl, K38, phiBTl and phiC3 1. [0011] In certain embodiments, the recombination between the second and the fourth RRS is mediated by a second site-specific recombinase. [0012] In certain embodiments, the landing pad further comprises a sequence encoding the site-specific recombinase. [0013] In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is a rodent cell. In certain embodiments, the cell is a human cell. In certain embodiments, the cell is an embryonic stem cell or a zygote. [0014] In certain embodiments, the selecting step comprises exposing the cell to a selective agent. In certain embodiments, the selective agent is ganciclovir. [0015] In another aspect, the present disclosure provides an isolated cell, the cell comprising a landing pad located at a RIDGE in the genome of the cell. The landing pad comprises sequentially (i) a first RRS, (ii) a negative selectable marker, and (iii) a second RRS. In certain embodiments, the landing pad further comprises a positive selectable marker. In certain embodiments, the landing pad further comprises a polynucleotide sequence encoding a site-specific recombinase that recognizes at least the first or the second RRS. In certain embodiments, the first and the second RRS are phiC31 attP (SEQ ID NO: 1). [0016] In yet another aspect, the present disclosure provides a nucleic acid construct comprising (a) an exchange cassette and (b) a selectable cassette. The exchange cassette comprises sequentially (i) a first RRS, (ii) the transgene of interest, and (iii) a second RRS. The selectable cassette comprises a negative selectable marker. In certain embodiments, the first and the second RRS are phiC3 1 attB (SEQ ID NO: 2). [0017] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, appended claims and accompanying drawings. BRIEF DESCRIPTION OF THE FIGURES [0018] FIG.
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