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Genome editing for scalable production of alloantigen-free lentiviral vectors for in vivo gene therapy.


ABSTRACT: Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large-scale manufacturing and raises concerns for in vivo applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell-derived polymorphic class-I major histocompatibility complexes (MHC-I) are incorporated into the LV surface and trigger allogeneic T-cell responses. By disrupting the beta-2 microglobulin gene in producer cells, we obtained MHC-free LV with substantially reduced immunogenicity. We introduce this targeted editing into a novel stable LV packaging cell line, carrying single-copy inducible vector components, which can be reproducibly converted into high-yield LV producers upon site-specific integration of the LV genome of interest. These LV efficiently transfer genes into relevant targets and are more resistant to complement-mediated inactivation, because of reduced content of the vesicular stomatitis virus envelope glycoprotein G compared to vectors produced by transient transfection. Altogether, these advances support scalable manufacturing of alloantigen-free LV with higher purity and increased complement resistance that are better suited for in vivo gene therapy.

SUBMITTER: Milani M 

PROVIDER: S-EPMC5666310 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Genome editing for scalable production of alloantigen-free lentiviral vectors for <i>in vivo</i> gene therapy.

Milani Michela M   Annoni Andrea A   Bartolaccini Sara S   Biffi Mauro M   Russo Fabio F   Di Tomaso Tiziano T   Raimondi Andrea A   Lengler Johannes J   Holmes Michael C MC   Scheiflinger Friedrich F   Lombardo Angelo A   Cantore Alessio A   Naldini Luigi L  

EMBO molecular medicine 20171101 11


Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large-scale manufacturing and raises concerns for <i>in vivo</i> applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell-derived polymorphic class-I major histocompatibility complexes (MHC-I) are incorporated into the LV surface and trigger allogeneic T-cell responses. By disrupting the beta-2 micr  ...[more]

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