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The TetraVecta™ System: A new tool kit enhancing lentiviral vector production for the next generation of gene therapies.

J Wright(1) B M Alberts(1) C Moore-Kelly(1) A Raposo(1) K A Mitrophanous(1) N G Clarkson(1) D C Farley(1)

1:Oxford BioMedica

Lentiviral vectors (LVs) remain the most established and efficient means to deliver transgenes to non-/dividing cells. The successes of ex vivo gene medicines using LVs are a springboard for their wider use ex vivo and their development for in vivo. The configuration of 3rd generation LV genomic sequences has not changed for two decades. To provide an LV platform better suited to wider use, we have generated the TetraVecta™ System with engineered LV genome sequences yielding improvements in four key areas.

Quality. The ‘2KO’ feature eliminates aberrant RNA splicing derived from the LV packaging signal during production, common to 3rd Gen LVs. This results in simplified vector RNA profiles, ensuring only full-length vector genomic RNA is converted into cDNA in target cells. 2KO-genomes also reduce transgene expression during production, especially when paired with the TRiP System™, minimising the presence of transgene protein within LVs particles.

Safety. The polyadenylation (polyA) sequences within 3rd Gen self-inactivating (SIN)-LTRs are suboptimal; our ‘sequence-upgraded polyA’ (supA)-LTRs improve polyA activity by >50 fold. This imparts transcriptional insulation to integrated LVs such that cellular gene ‘read-in’ and transgene ‘read-out’ are greatly minimised. Transgene expression is also increased 2-3 fold.

Capacity. The ‘MaxPax’ form of the TetraVecta™ system has increased payload capacity thanks to removal of ~1kb of backbone sequence and is also rev-independent.

Production. Combining several/all of these features, alongside using novel production enhancers, simplifies the Upstream and Downstream aspects of LV production, reducing time spent on process development and often resulting in greater yields.

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