Reginald Tran
PhD Proposal Presentation
Date: Friday, October 17th, 2014
Time: 9:30am
Location: IBB, Room 1128 (Suddath Room)

Advisor: Wilbur Lam, MD, PhD (Georgia Institute of Technology/Emory University)

Committee Members:
J. Brandon Dixon, PhD (Georgia Institute of Technology)
Christopher B. Doering, PhD (Emory University)
Joseph M. Le Doux, PhD (Georgia Institute of Technology/Emory University)
Todd Sulchek, PhD (Georgia Institute of Technology)

Title: A Microfluidics-based Paradigm for Clinical Lentivector Gene Transfer

Abstract:

Hematopoietic stem cells and immunocompetent T-cells hold the potential to correct several inherited genetic blood disorders and cancer, respectively, through ex vivo gene therapy utilizing lentiviral vectors. Lentiviral vectors provide an attractive method for cell transduction, the process of inserting foreign DNA into a cell with a viral vector, due to their ability to infect non-dividing cells with stable integration of DNA. However, progress in the field has been severely hampered by low transduction efficiencies in current platforms despite various efforts to improve virus-cell interactions. Previous studies have shown that viral transduction is a diffusion-limited process governed by Brownian motion. With current methods, due to the short half-life of these self-inactivating viruses, many of the viral particles will never reach the target cells before decaying, resulting in the observed low rates of gene transfer. Microfluidic devices provide an ideal platform to overcome these barriers by leveraging high surface area to volume ratios. This project will focus on designing a microfluidic-based platform to enhance lentiviral transduction efficiency in non-adherent cells, optimizing parameters that allow for greater virus-cell interactions for scaling up toward clinically-relevant levels, and applying these techniques toward the transduction of human CD34+ hematopoietic progenitor cells and effector cytotoxic T cells, the target cell types of many clinical gene therapy trials.

The goal of this work is to develop strategies to enhance the lentiviral transduction efficiency for clinical gene therapy. The overall objective of this proposal is to design microfluidic devices to promote more effective transport of viral particles to target cells. The central hypothesis of this proposal is that the amount of virus necessary to achieve therapeutic levels of cell transduction can be significantly reduced by leveraging various microfluidic features.