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Transposition from a Gutless Adeno-Transposon Vector Stabilizes Transgene Expression in Vivo

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Transposition from a Gutless Adeno-Transposon Vector Stabilizes Transgene Expression in Vivo RESEARCH ARTICLE Transposition from a gutless adeno-transposon vector stabilizes transgene expression in vivo Stephen R.Yant, Anja Ehrhardt, Jacob Giehm Mikkelsen, Leonard Meuse, Thao Pham, and Mark A. Kay* Published online: 16 September 2002, doi:10.1038/nbt738 A major limitation of adenovirus-mediated gene therapy for inherited diseases is the instability of transgene expression in vivo, which originates at least in part from the loss of the linear, extrachromosomal vector genomes. Herein we describe the production of a gene-deleted adenovirus–transposon vector that stably maintains virus-encoded transgenes in vivo through integration into host cell chromosomes. This system uti- lizes a donor transposon vector that undergoes Flp-mediated recombination and excision of its therapeutic payload in the presence of the Flp and Sleeping Beauty recombinases. Systemic in vivo delivery of this sys- tem resulted in efficient generation of transposon circles and stable transposase-mediated integration in mouse liver. Somatic integration was sufficient to maintain therapeutic levels of human coagulation Factor IX for more than six months in mice undergoing extensive liver proliferation. These vectors combine the versatili- ty of adenoviral vectors with the integration capabilities of a eukaryotic DNA transposon and should prove use- ful in the treatment of genetic diseases. http://www.nature.com/naturebiotechnology Successful gene therapy for genetic diseases will require two major most active of these members is the Tc1-like element Sleeping attributes from a single vector: high-efficiency gene delivery and life- Beauty, which was reconstructed from pieces of an ancient fish ele- long therapeutic gene expression. Among the vector technologies ment16,17. This transposon undergoes cut-and-paste transposition currently available, recombinant adenovirus (Ad) vectors remain through a DNA intermediate, a process that requires the binding of attractive vehicles for therapeutic gene transfer. These vectors can be the Sleeping Beauty transposase (SB) to short direct-repeat sequences grown to high titers, exhibit a broad tropism, can transduce dividing embedded in the terminal inverted repeats (IRs) of the element17. and nondividing cells, and are one of the most efficient vehicles for Transposition is catalyzed entirely by the SB transposase and always in vivo gene delivery1. However, early versions of Ad vectors were occurs into a TA target dinucleotide, which is duplicated upon inser- plagued by toxicity and immunogenicity due to in vivo synthesis of tion by cellular DNA repair pathways. Previously, we reported that viral antigens from genes still contained in the vector2–4. SB transposase expression allows plasmid-based transposons to inte- To overcome these problems, the Cre-loxP helper-dependent grate safely and stably into mouse liver DNA18. Importantly, transpo- © Group 2002 Nature Publishing (HD) system was developed to generate recombinant adenoviruses sition was sufficient to maintain long-term transgene expression in which all viral coding sequences have been deleted5. Because the in vivo, even during periods of extensive liver regeneration19. Despite HD vector requires only the inverted terminal repeats (ITRs) and its enormous potential, the inability to deliver this integrating system packaging signal for proper DNA replication and virus assembly, in vivo efficiently in a clinically relevant manner remains a formida- these vectors can accommodate up to 35 kilobases of foreign DNA. ble obstacle to its practical implementation in basic research and Importantly, these gene-deleted vectors exhibit little to no toxicity human gene therapy applications. in vivo and can produce therapeutic amounts of various proteins in In this report, we have incorporated the SB integration machinery animals6–12. Nonetheless, transgene expression from these non- into Ad vectors to combine the major advantages of each system. In replicative HD vectors still remains unstable in vivo, declining by as the process, we have identified a new limitation in the SB system, much as 95% over a period of one year11. Recent in vitro studies indi- namely that to transpose, SB transposons need to circularize. cate that the frequency of genomic integration of Ad vectors is quite Consequently, we have generated gene-deleted Ad vectors that low13,14, suggesting that transgene instability originates at least in release circular transposons from the linear Ad genome through the part from the loss of the linear, extrachromosomal HD genome in activities of the Flp/FRT recombination system. These high-capacity transduced cells. adeno-transposon vectors were characterized in mice and could One approach to circumvent this obstacle is to incorporate a DNA facilitate the somatic integration of virus-encoded transgenes into transposon into the Ad vector to maintain Ad-encoded transgenes in host cell chromosomes, resulting in greatly improved longevity of dividing cells through genomic integration. Although integration Ad-based gene expression in vivo. itself does not always guarantee long-term gene expression, it is the most reliable way to maintain genetic material within a cell over Results time. Currently, the only DNA elements reported to function within Analysis of Ad-based transposition in vitro and in vivo. To determine the context of mammalian cells are members of the Tc1/mariner whether the Sleeping Beauty transposon system could function in the family of transposable elements15. Recent studies indicate that the context of an adenovirus, we studied Ad-based transposition in vivo Departments of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, CA 94305-5208. *Corresponding author ([email protected]). www.nature.com/naturebiotechnology • OCTOBER 2002 • VOLUME 20 • nature biotechnology 999 RESEARCH ARTICLE A A B B C Figure 1. Analysis of transposition from E1/E3-deleted adenoviruses and linear transposon DNA. (A) Structures of the E1/E3-deleted transposition Figure 2. The adeno-transposon system. (A) Overview of the strategy to vectors Ad-SB and Ad-ThAAT for in vivo delivery of the Sleeping Beauty facilitate transposition from a helper-dependent adenovirus vector. An Ad http://www.nature.com/naturebiotechnology transposase–transposon system. 5’ITR and 3’ITR, Left and right termini vector containing a Sleeping Beauty transposon remains of adenovirus type 5, respectively; RSV, Rous sarcoma virus long terminal extrachromosomal in SB-expressing cells because the transposase cannot repeat promoter; SB, Sleeping Beauty transposase; pA, polyadenylation efficiently act upon linear DNA structures. When the transposon is flanked signal; E1/E3, adenovirus type 5 early regions 1 and 3, respectively; IR, by a pair of Flp recognition target (FRT) sequences, the Ad vector Sleeping Beauty inverted repeat sequences; hAAT, human α1-antitrypsin undergoes conditional rearrangement in cells co-expressing the Flp cDNA. (B) Long-term Ad-based transposon expression in mice in the recombinase. This results in excision of the transposon from the Ad presence and absence of transposase. C57Bl/6 mice (n = 5 mice per genome and its circularization by Flp-mediated recombination. In contrast group) were injected through the tail vein with 2 × 109 transducing units to their linear counterparts, these circular elements actively undergo DNA- (TU) AdThAAT together with 6 × 109 TU of either AdSB (̆) encoding the mediated transposition, resulting in stable insertion of the transposon into SB transposase or Ad-null (२) as a control. (C) Transposition efficiency host cell chromosomes. Prom, Mammalian promoter. (B) Structure of from circular and linear transposable elements in cultured mammalian helper-dependent transposition vectors. We used a two-vector approach to cells. Cells were transfected with transposon DNA and, when applicable, analyze transposition from gutless Ad vectors in vivo. This strategy a helper plasmid encoding either wild-type (SB) transposase or a employs the use of one vector to provide the Flp and SB recombinases catalytically inactive mutant (mSB) transposase as a control. Transfected that act upon a second Ad vector containing an SB donor transposon. cells were growth-selected in G418 for 14 days, fixed, stained, and HD-SB-Flp and HD-mSB-Flp both encode the enhanced Flp recombinase counted. The number of G418-resistant (G418r) colonies (mean ± s.d.) (Flpe) necessary for conditional vector rearrangement, but HD-mSB-Flp obtained after three independent transfections is shown. SV40, Simian cannot support transposition because of an inactivating mutation © Group 2002 Nature Publishing virus promoter; neo, neomycin-phosphotransferase gene. Left panel, introduced into the transposase gene. The donor vectors HD-FRT-Tnori, transposition of a supercoiled neo-marked transposon in HeLa cells; HD-Tnori, HD-FRT-TLacZ, HD-TLacZ, and HD-FRT-ThFIX contain donor middle panel, transposition frequency of a linearized neo-marked element transposons encoding kanamycin (3.4 kb), β-galactosidase (5.5 kb), or in HeLa cells; right panel, transposition of a linear neo-marked transposon human Factor IX (4.5 kb), respectively.The intron-containing transgenes with (+IR) and without (–IR) flanking inverted repeats in HeLa cells present in the LacZ and hFIX constructs are initially split and thus remain constitutively expressing the SB transposase (HeLa-SB)49. inactive until Flp-mediated circularization restores the correct reading frame. HD-Tnori and HD-TLacZ are control vectors that lack
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