PhD Defense by Reginald Tran

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  • Date/Time:
    • Wednesday October 26, 2016
      3:00 pm - 5:00 pm
  • Location: Marcus Nanotechnology Building, Room 1116-1118
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Summary Sentence: A Microfluidics-based Paradigm for Clinical Lentivector Gene Transfer

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~~Reginald Tran
PhD Defense Presentation
 
Date: Wednesday, October 26, 2016
Time: 3:00 pm
Location: Marcus Nanotechnology Building, Room 1116-1118
 
Advisor: Wilbur Lam, MD, PhD (Emory University/Georgia Institute of Technology)
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
 
HIV-derived lentiviral vectors (LVs) have enormous potential to correct genetic disorders and improve T cell mediated cancer therapies. LVs are safer and more effective than other genetic engineering approaches but the expensive and low yield manufacturing process hampers their use. Lengthy ex vivo cell transduction protocols utilizing large quantities of LV are often required to achieve the desired clinical outcomes. Ongoing clinical trials routinely use an entire LV production run to dose a single patient. The goal of this work was to improve LV transduction by designing a microfluidic platform that could adapt to current cell transduction protocols. We hypothesized that utilizing a microfluidic, mass transport-mediated approach would overcome the diffusion limitations of existing transduction platforms, enabling enhanced LV gene transfer kinetics and efficiency. Using hematopoietic cell lines, primary human T cells, and primary murine hematopoietic stem and progenitor cells, we demonstrated that microfluidic transduction occurs up to 5-fold faster and requires as little as 1/20th of LV requirements observed in conventional clinical transduction protocols. Furthermore, in vivo application of microfluidics using hematopoietic stem and progenitor cells of C57BL/6J hemophilia A mice transduced with factor VIII-encoding LV and transplanted into hemophilic donors demonstrated that LV usage and transduction time is significantly reduced using our platform without negatively impacting cell engraftment or mouse survival. Overall, this work broadens the current understanding of LV transduction and provides an alternative method to enhance transduction that can be incorporated with other transduction enhancement strategies, which is an important step to achieving routine clinical implementation and globalization of gene therapy.
 

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  • Created By: Tatianna Richardson
  • Workflow Status: Published
  • Created On: Oct 12, 2016 - 2:52pm
  • Last Updated: Oct 12, 2016 - 2:52pm