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000157016 1001_ $$0P:(DE-He78)3391c5ad790ea5359189d11f073fb103$$aBozza, Matthias$$b0$$eFirst author$$udkfz
000157016 245__ $$aNovel Non-integrating DNA Nano-S/MAR Vectors Restore Gene Function in Isogenic Patient-Derived Pancreatic Tumor Models.
000157016 260__ $$aNew York, NY$$bNature Publishing Group$$c2020
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000157016 520__ $$aWe describe herein non-integrating minimally sized nano-S/MAR DNA vectors, which can be used to genetically modify dividing cells in place of integrating vectors. They represent a unique genetic tool, which avoids vector-mediated damage. Previous work has shown that DNA vectors comprising a mammalian S/MAR element can provide persistent mitotic stability over hundreds of cell divisions, resisting epigenetic silencing and thereby allowing sustained transgene expression. The composition of the original S/MAR vectors does present some inherent limitations that can provoke cellular toxicity. Herein, we present a new system, the nano-S/MAR, which drives higher transgene expression and has improved efficiency of establishment, due to the minimal impact on cellular processes and perturbation of the endogenous transcriptome. We show that these features enable the hitherto challenging genetic modification of patient-derived cells to stably restore the tumor suppressor gene SMAD4 to a patient-derived SMAD4 knockout pancreatic cancer line. Nano-S/MAR modification does not alter the molecular or phenotypic integrity of the patient-derived cells in cell culture and xenograft mouse models. In conclusion, we show that these DNA vectors can be used to persistently modify a range of cells, providing sustained transgene expression while avoiding the risks of insertional mutagenesis and other vector-mediated toxicity.
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000157016 7001_ $$0P:(DE-He78)9b97ca569bcb00dfda69382bc7261700$$aGreen, Edward W$$b1$$udkfz
000157016 7001_ $$0P:(DE-HGF)0$$aEspinet, Elisa$$b2
000157016 7001_ $$0P:(DE-He78)3735edce41649376fec34cf8b3a1843d$$aDe Roia, Alice$$b3$$udkfz
000157016 7001_ $$0P:(DE-He78)0812f68beb25392984d3abbe3c58b6d2$$aKlein, Corinna$$b4$$udkfz
000157016 7001_ $$0P:(DE-He78)03fd0ab6ad061c771968971670c391e2$$aVogel, Vanessa$$b5$$udkfz
000157016 7001_ $$0P:(DE-He78)81ae96953d6149e4307057d71a190019$$aOffringa, Rienk$$b6$$udkfz
000157016 7001_ $$aWilliams, James A$$b7
000157016 7001_ $$0P:(DE-He78)0f44fcb0b05507b0a20b175f7ba9ed1c$$aSprick, Martin$$b8$$udkfz
000157016 7001_ $$0P:(DE-He78)15dff5647002b4dcfe892b251cd14b62$$aHarbottle, Richard$$b9$$eLast author$$udkfz
000157016 773__ $$0PERI:(DE-600)2863173-0$$a10.1016/j.omtm.2020.04.017$$gVol. 17, p. 957 - 968$$p957 - 968$$tMolecular therapy Methods & clinical development$$v17$$x2329-0501$$y2020
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