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Engineering Therapies that Evolve to Autonomously Control Epidemics

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Technical Report

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The J. David Gladstone Institutes San Francisco United States

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The overarching aim of our seedling effort was to de-risk the idea that viruses could be engineered into therapeutics, known as Therapeutic Interfering Particles TIPs, using the virus HIV as a model system. By engineering TIP prototypes that were shown to reduce HIV levels 10X in cell-culturewhile having no effect on the viability of healthy, uninfected cellswe directly achieved this aim Aim I of our proposal. The secondary aim Aim II of the proposal was to demonstrate, via mathematical modeling, that engineered TIPs could have indefinite, population-scale impact. To achieve this aim, we developed novel multi-scale models that connected the measured within-cell TIP dynamics achieved in Aim I with the predicted population-scale impact of these TIP prototypes on HIV prevalence levels. We further calculated cellular design constraints e.g., genomic RNA expression levels to guide the development of TIPs with predicted population-scale efficacy. Finally, we demonstrated the evolutionary robustness of TIPs against a key route of HIV mutational escape. Our modeling results de-risking the TIP approach were published in PLoS Computational Biology this past year.

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  • Medicine and Medical Research

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