Characterization of recombinant human factor IX expressed in transgenic mice and in derived trans-immortalized hepatic cell lines.

Jallat, S.; Perraud, Frédéric; Dalemans, Wilfried; Balland, Alain; Dieterlé, A; Faure, Thérèse; Meulien, Pierre; Pavirani, Andréa

doi:10.1002/j.1460-2075.1990.tb07529.x

Cited by 61 publications

(41 citation statements)

References 41 publications

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“…This is consistent with in vitro data generated by us 47 and by others 48 in nonhepatocyte cell types, showing that the cell's capacity to execute critical posttranslational modifications (eg, ␥-carboxylation) can be saturated, resulting in production of F.IX protein with reduced specific activity. Our results are at odds with data published on the first F.IX transgenic mice by Jallat et al, 49 who found that mice expressing up to 25 g/mL hF.IX had normal specific activity. These investigators were attempting to measure specific activity of hF.IX on a background of normal levels of murine F.IX.…”

Section: Discussioncontrasting

confidence: 99%

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Sabatino

Armstrong

Edmonson

et al. 2004

Blood

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Animal models have been critical to the development of novel therapeutics in hemophilia. A deficiency of current murine models of hemophilia B is that they are all due to gene deletions, a type of mutation that is relatively rare in the human hemophilia population. We generated mice with a range of mutations in the Factor IX (F.IX) gene; these more faithfully reflect the types of mutations that cause disease in the human population. Transgenic mice expressing either wild-type human F.IX (hF.IX), or F.IX variants with premature translation termination codons, or missense mutations, under the control of the murine transthyretin promoter, were generated and crossed with mice carrying a large deletion of the murine F.IX gene. Gene copy number, F.IX transcript levels in the liver, intrahepatocyte protein expression, and circulating levels of F.IX protein in the mice were determined and compared with data generated by transient transfection assays using the same F.IX variants. Mice were injected with a viral vector expressing hF.IX and displayed a range of immune responses to the transgene product, depending on the underlying mutation. These new mouse models faithfully mimic the mutations causing human disease, and will prove useful for testing novel therapies for hemophilia.

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Section: Discussioncontrasting

confidence: 99%

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Sabatino

Armstrong

Edmonson

et al. 2004

Blood

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“…These results indicate that, at least in vitro, this distal sequence is not involved in regulating grik5 transcription and tissue-specific expression. Transcriptional regulatory elements of eukaryotic genes are found not only in their 5Ј upstream region, but also within their introns (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). These sequences can act as transcriptional enhancers (27,28,30,33) or can be required for appropriate tissue-or cell-specific expression (25,26,34).…”

Section: Discussionmentioning

confidence: 99%

Gene Structure of the Rat Kainate Receptor Subunit KA2 and Characterization of an Intronic Negative Regulatory Region

Huang

Gallo

1997

Journal of Biological Chemistry

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We have isolated and analyzed the structure of the gene grik5 (glutamate receptor ionotropic kainate 5), encoding the rat kainate receptor subunit KA2. Six overlapping DNA fragments containing the entire grik5 gene were identified in a rat genomic library. grik5 is a unique gene composed of 20 exons that together span over 54 kilobases (kb). Reporter gene analysis demonstrated that 2 kb of grik5 5-flanking sequence confers tissue-specific expression on a chloramphenicol acetyltransferase gene in vitro. We show that (i) the first intron of grik5 (3.4 kb) inhibited transcription of the chloramphenicol acetyltransferase gene driven by the 2-kb grik5 5-flanking region; (ii) the negative regulatory element was located within 500 bp of the 3-end of intron 1, and this 500-bp fragment selectively bound nuclear proteins isolated from neural and nonneural cells; (iii) the effect of the negative regulatory element on grik5 transcription was orientation-and distance-independent; and (iv) a 24-nucleotide sequence (CTTTCTGTGGC-CTCTGACCTTTCC) was identified as the binding site for nuclear proteins within the 500-bp fragment, as determined by footprinting and gel shift assays. We conclude that an intronic element that displays features of a silencer modulates grik5 transcription.

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“…A 251 bp sequence of the genomic human gA-I containing the complete 5 0 -UTR including the first apo A-I intron was subcloned to generate pTG14681-AT.A-I intron.cDNA.E 4 . Multiple sublconing steps using a truncated human FIX intron 12,53,54 isolated from pGEM-FIX-intron by ClaI and NotI digestion led to the formation of pTG14681-AT.FIX intron.cDNA.E 4 .…”

Section: Construction Of Expression Cassettes For Hepatocytedirected mentioning

confidence: 99%

Direct comparison of hepatocyte-specific expression cassettes following adenoviral and nonviral hydrodynamic gene transfer

et al. 2008

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Hepatocytes are a key target for treatment of inborn errors of metabolism, dyslipidemia and coagulation disorders. The development of potent expression cassettes is a critical target to improve the therapeutic index of gene transfer vectors.Here we evaluated 22 hepatocyte-specific expression cassettes containing a human apo A-I transgene following hydrodynamic transfer of plasmids or adenoviral transfer with E1E3E4-deleted vectors in C57BL/6 mice. The DC172 promoter consisting of a 890 bp human a 1 -antitrypsin promoter and two copies of the 160 bp a 1 -microglobulin enhancer results in superior expression levels compared to constructs containing the 1.5 kb human a 1 -antitrypsin promoter, the 790 bp synthetic liver-specific promoter or the DC190 promoter containing a 520 bp human albumin promoter and two copies of the 99 bp prothrombin enhancer. The most potent expression cassette consists of the DC172 promoter upstream of the transgene and two copies of the hepatic control region-1. Minicircles containing this expression cassette induce persistent physiological human apo A-I or human factor IX levels after hydrodynamic transfer. In conclusion, in this comparative study of 22 hepatocyte-specific expression cassettes, the DC172 promoter in combination with two copies of the hepatic control region-1 induces the highest expression levels following hydrodynamic and adenoviral transfer.

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Characterization of recombinant human factor IX expressed in transgenic mice and in derived trans-immortalized hepatic cell lines.

Cited by 61 publications

References 41 publications

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Gene Structure of the Rat Kainate Receptor Subunit KA2 and Characterization of an Intronic Negative Regulatory Region

Direct comparison of hepatocyte-specific expression cassettes following adenoviral and nonviral hydrodynamic gene transfer

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