Genes, or snippets of DNA, are instructions that are read by cells in our body to produce proteins that carry out a plethora of life's essential functions. Gene therapy relies on modifying defective genes or introducing new genes, thereby restoring functionality or introducing new functionality. Gene therapy offers a therapeutic potential against a wide variety of ailments ranging from genetic diseases to cancer and infectious diseases. One of the major hurdles of gene therapy is gene delivery; DNA molecules carrying the gene cannot cross the formidable barrier of the cell membrane and enter cells to exert its therapeutic potential. Methods of introducing genes to cells, that are both efficient and safe, are needed. Electroporation is one such method that relies on applying an electric field to transiently permeabilize the cell membrane and introduce foreign molecules, including genes, to cells. Although safe, electroporation is not efficient at introducing genes to cells in our body. This action - GETPolPhys or Gene Electro-Transfer through the lens of polymer physics - was aimed at developing a fundamental understanding of gene delivery using electroporation. Using the fundamental understanding, major barriers to electroporation mediated gene delivery (or gene electro-transfer) were identified and overcome.
Gene therapies have so far relied on viruses to deliver the genes to cells. A major problem of virus based gene therapy is safety; administering viruses leads to severe toxicity [1]. Another major problem is the cost; a virus based gene therapy for treatment of Spinal Muscular Atrophy costs around 2 millions euros [2]. The exorbitant costs of such therapies prevents its widespread adoption, especially amongst the low and middle income countries. Delivering chemotherapeutics using electroporation has proven to be safe, effective and easy to use [3]. Moreover, production of DNA molecules used in gene-electrotransfer has only 1/3rd the cost of virus production [4]. However, gene-electrotransfer is limited by its efficiency [5]. Improving the efficiency of gene-electrotransfer by fundamentally understanding the barriers will unleash the full potential of gene therapy in the clinics, allow its wide-spread adoption owing to its low cost of administration and offer a safer route to gene therapy.
The overall objective of this action was to obtain a fundamental understanding of how DNA molecules overcome the barriers of (a) the extracellular space and (b) the cell membrane during gene electro-transfer using principles of polymer physics and statistical mechanics. The use of these principles are indispensable to understanding the mechanisms of gene-electrotransfer, and an understanding based on these principles will lead to enhancing the efficiency of gene electro-transfer from first principles as opposed to the current time and resource intensive approach of trial-and-error. A parallel goal of the action was to also develop the skills of the fellow in the field of pre-clinical research and clinical aspects of gene therapies and advance his career in translation of therapies towards clinics.
[1] Wilson, J. M., & Flotte, T. R., Genetic Engineering & Biotechnology News 2020, 40(8), 14-16. [2] Nuijten, M., Journal of Market Access & Health Policy 2022, 10(1), 2022353. [3] Cemazar, M., & Sersa, G., Bioelectricity 2019, 1(4), 204-213. [4] Ran, T., Eichmüller et al., International journal of cancer 2020, 147(12), 3438-3445. [5] Sachdev, S. et al., Bioelectrochemistry 2022, 144, 107994.
