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Engineering Macrophages for Cell-Based Therapies

  • Author(s): Lee, Simon
  • Advisor(s): Szoka, Francis C
  • et al.
Abstract

In the last decade, the promise of cell-based therapy has come closer to fruition. Although macrophages (MΦ) play important roles in immunity, development and homeostatic tissue maintenance, they have not yet been incorporated into this cell therapy revolution. This reality may change due to a better understanding of MΦ development, plasticity and diverse phenotypical behaviors. As such, there is now the information needed to devise and develop MΦ cell-based therapies.

In this dissertation, I describe the engineering approaches I employed to improve and develop MΦ for cell-based therapies. I first focused on developing a means of generating large numbers of functional MΦ in vitro by the reversible expression of the Hoxb8 transcription factor. I next investigated the biodistribution and survival of transplanted Hoxb8 dependent progenitors (HDP) and macrophages arising from them (HDP-MΦ) in immunocompetent BALB/c and immunodeficient NCG mice. This was enabled by incorporating a number of genetic modifications into the HDP including: constitutively active GMCSFR, luciferase and an inducible IRF8, and by pretreating animals with liposomal clodronate. This combination of factors led to improving the post-transplantation survival of HDP from <1 day to 7 days in BALB/c mice. In addition, I engineered HDP to overexpress iduronidase (IDUA) as a potential cell vector to deliver therapeutic doses of IDUA in the mouse for the treatment of Hurlers Syndrome. These techniques and results described here can guide new approaches for developing novel MΦ-based therapeutics.

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