Electric pulses could make gene therapy more effective

Delivering short electrical pulses to cells has been shown to increase their susceptibility to take in gene therapy, potentially reducing the dosage required.

Researchers subjected cells to short electrical pulses, which led the cells to take in 50 times more gene therapy compared to cells exposed to the gene therapy alone. The project began almost ten years ago, when, Dr Hans Sollinger, a transplant surgeon at the University of Wisconsin-Madison, who died in May 2023, developed a gene therapy to boost insulin production in type 1 diabetes patients. Dr Sollinger teamed up with electrical and computing engineers at the University in order to develop a way to overcome the limitations of the gene therapy delivery.

'What we started talking about was local, targeted delivery and whether there was a way of getting the treatment DNA directly into the liver without passing it through the entire body and triggering the immune system,' said Professor Susan Hagness, an electrical engineer at the University of Wisconsin-Madison. 'And whether we could use electric pulses in order to make this delivery process more efficient and dramatically reduce the dose needed.'

An 80-millisecond electrical pulse was delivered to liver cells using a pair of electrodes, while the cells were simultaneously exposed to gene therapy virus particles encapsulating a green fluorescent protein – a commonly used experimental tool for easy visualisation under a microscope. The expression of the fluorescent protein was examined 48 hours later. The electrically stimulated cells exhibited over 50 times more fluorescence than non-stimulated cells, yet the cells showed no permanent damage in response to the pulse.

Building on this finding, published in PLOS ONE, PhD student Yizhou Yao, also at the University of Wisconsin-Madison and lead author of the paper, discovered why liver cells become more receptive to gene therapy delivery when exposed to electrical pulses. Yao demonstrated that the viral particles remain unchanged during the process and instead the electrical pulse creates tiny holes in the cell membrane. However, further research is still needed to fully understand the exact mechanism.

'There's enough known about electric pulsing that I think we could confidently state that it is opening nanopores through the cell membrane,' said Professor John Booske, emeritus professor in electrical and computer engineering at the University of Wisconsin-Madison. 'But then Yao got this remarkable result, and it dawned on us that virus particles are in general bigger and more complex than bare molecular particles and they already have their own way of getting inside cells. So, we don't really know if it's the pores opening that has anything to do with it directly or indirectly.'

The electrical engineers are hopeful the technique could progress to clinical trials, and with the ability to lower the required dose could lead to improving safety and reducing the cost of gene therapies.