Grants and Contracts Details
Description
Intellectual Merit:
Human gene therapy holds tremendous promise for treatment of conditions from cystic
fibrosis to cardiovascular disease to cancer, but clinical implementation has been hindered by
the lack of safe and efficient methods for delivery of genetic material. Most gene therapy trials
have employed recombinant viruses, which possess hierarchical structure and functions
evolved for efficient gene delivery, but present serious safety concerns. Non-viral vectors, such
as cationic polymers, can be designed to be biocompatible and non-immunogenic; allow celltype
specificity via attachment of targeting ligands; and are more robust and amenable to
formulation. However, non-viral vectors lack the delivery efficiency necessary for clinical use.
Although the chemistry of polymeric gene delivery agents has been the focus of much
research for more than two decades, the fabrication and resulting structure of polymer/DNA
complexes (polyplexes) has received little attention. Conventional polyplex assembly methods,
via simple mixing, allow limited control of polyplex size, size uniformity, or spatially defined
arrangement of the DNA and polymer(s). Enhanced control of assembly—including the
capability of producing multilayered polyplexes comprising two or more synthetic agents that
each provide specific functionality—will be critical to the design of non-viral vectors with
clinically relevant activity.
We are developing microfluidic systems for construction of monodisperse, multilayered,
multifunctional non-viral vectors. The devices bring solutions of plasmid DNA and polycations
into contact under laminar flow providing control of polymer/DNA stoichiometry and interaction
times and allowing introduction of multiple materials in a sequential fashion and defined spatial
arrangement. The goals of the project are: (1) to construct a microfluidic polyplex assembly
device and demonstrate control of polyplex size and uniformity; (2) to design a secondgeneration
device for layer-by-layer (LbL) assembly of multifunctional polyplexes comprising
plasmid DNA and polymers of alternating charge; and (3) to demonstrate the efficiency of
monodisperse and LbL polyplexes for gene delivery to human cell lines.
Broader Impacts:
The proposed research could ultimately impact basic biological research requiring
efficient gene delivery to cells in culture as well as development of human gene therapy.
Perhaps more importantly, however, this project represents a first attempt (to our knowledge) to
develop methods for reproducible, robust manufacture of multi-layered, multifunctional synthetic
gene delivery agents. The aims of the project, therefore, are designed not to merely generate an
effective vector, but to develop new understanding of vector assembly, how it can be controlled,
and its impact on vector performance. The main impact of this project may be methods and
devices that can be readily adopted by researchers around the globe.
The proposed project will also impact education for pre-college, undergraduate, and
graduate students. This interdisciplinary project is expected to provide excellent training for
graduate and undergraduate students in the PI’s lab. Students at all levels will be recruited to
this project from engineering, pharmaceutical sciences, and basic science disciplines. In
addition, the PI and undergraduate students will develop a module for outreach to high school
girls through UK’s Girls in Engineering, Mathematics and Science program that will introduce
students to chemical engineering principles of fluid dynamics.
Status | Finished |
---|---|
Effective start/end date | 7/15/14 → 6/30/18 |
Funding
- National Science Foundation: $300,000.00
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