iMATCH: an integrated modular assembly system for therapeutic combination high-capacity adenovirus gene therapy
نویسندگان
چکیده
Adenovirus-mediated combination gene therapies have shown promising results in vaccination or treating malignant and genetic diseases. Nevertheless, an efficient system for the rapid assembly incorporation of therapeutic genes into high-capacity adenoviral vectors (HCAdVs) is still missing. In this study, we developed iMATCH (integrated modular HCAdVs) platform, which enables generation production HCAdVs encoding combinations high quantity purity within 3 weeks. Our cloning facilitates up to four expression cassettes integration HCAdV genomes with defined sizes. Helper viruses (HVs) purification protocols were optimized produce distinct capsid modifications unprecedented (0.1 ppm HVs). The constitution HCAdVs, adapters targeting a shield trimerized single-chain variable fragment (scFv) reduced liver clearance, mediated cell- organ-specific HCAdVs. 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Enzymatic molecules several hundred kilobases.Nat. Methods. 343-345Crossref (4367) done sequentially simultaneously, allowing 1 day. Plasmid-encoded, correctly assembled antibiotic resistance sequencing, confirming than 80%. verify approach, plasmid. Cells transfected showed similar greater compared reporter-encoding transfection S1). Once desired assembled, additional set (pC4HSU overlaps) well-characterized (pC4HSU)35Sandig Scholar,48Flynn Buckler J.M. Tang Kim Dichek superior endothelial cell-targeted therapy.Mol. 2121-2129Abstract (17) 1B). Depending size digested PmeI/PacI, PmeI/XmaI, PmeI S2A). Each resulting S2B) pC4HSU generated AscI, AscI/NotI, AscI/SwaI digest prior S2C). Linearization releases 0, 4.5, 9 “stuffer DNA” S2D), adapt HCAdV. biophysical properties, independent size. increase (FspI) introduced Backbone fragments release, re-circularized, false-positive clones presence lack payloads. reason, FspI parallel enzymes release. two (linearized pC4HSU) transformation S2E), efficiencies 85% positive obtained representative construct S2F). amplification modifications, hexon prevent X-mediated infection41Xu modification RGD motif penton integrin-mediated (off-target infection49Shayakhmetov D.M. Eberly Li Z.Y. Lieber Deletion motifs affects both internalization endosome escape serotype 35 knobs.J. 2005; 79: 1053-1061Crossref (91) Scholar). These readily enable capsids 1C) without need modify genome. advantageous uptake, off-target approaches.37Barry adapters38Dreier again original 1D). Retargeted additionally covered shield, formed scFv antibodies.43Schmid preparations kept possible, unavoidable HV, causes response HC-infected recipient On hand, 2A), they necessary balanced concentrations minimize contamination, had even encapsulation signal,35Sandig
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ژورنال
عنوان ژورنال: Molecular therapy. Methods & clinical development
سال: 2021
ISSN: ['2329-0501']
DOI: https://doi.org/10.1016/j.omtm.2021.01.002