Abstract

The demand for viral vectors is expected to soon exceed current production capacities, driven by the increasing number of approved and advanced-phase cell and gene therapies. Current manufacturing processes for viral vectors are hindered by high costs and suboptimal yields. This talk will demonstrate how process systems engineering tools can address key challenges in the manufacturing of recombinant adeno-associated virus (rAAV), a pivotal viral vector for in vivo gene therapy. A mechanistic model is first developed to identify the intracellular bottlenecks to rAAV formation in the Sf9/baculovirus expression vector system (BEVS), an important platform for the production of commercial rAAV-based therapies. The model suggests genetic modifications to the platform that lead to a two-fold increase of per-cell rAAV productivity upon experimental validation. Next, optimal process conditions for continuous rAAV manufacturing in the BEVS are identified using a novel numerical method for solving systems of partial differential equations. The in silico-optimized process is validated in a cascade of bioreactors, demonstrating for the first time sustained high-titer rAAV production for over 20 days. Finally, a novel machine learning model is introduced for real-time rAAV titer quantification based on single-cell biophysical measurements, offering an innovative tool for enhanced process monitoring and control in rAAV manufacturing.

Speaker Bio

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Francesco Destro is a Postdoctoral Associate at the Department of Chemical Engineering and at the Center for Biomedical Innovation at MIT, where he conducts research into process systems engineering and advanced biopharmaceutical manufacturing. He obtained a Ph.D. in Chemical Engineering from the University of Padova in 2022, with a dissertation that received the European Federation of Chemical Engineering’s Excellence Award in Recognition of an Outstanding PhD Thesis on Computer Aided Process Engineering in 2024. He further consolidated his research expertise in systems engineering and (bio)pharmaceutical manufacturing as a Visiting Scholar at Siemens Process Systems Engineering (London, UK) in 2019 and at Purdue University in 2020 and 2022.