Background and Objective: The paper focuses on the numerical strategies to optimize a plasmid DNA delivery protocol, which combines hyaluronidase and electroporation. Methods: A well-defined continuum mechanics model of muscle porosity and advanced numerical optimization strategies have been used, to propose a substantial improvement of a pre-existing experimental protocol of DNA transfer in mice. Our work suggests that a computational model might help in the definition of innovative therapeutic procedures, thanks to the fine tuning of all the involved experimental steps. This approach is particularly interesting in optimizing complex and costly protocols, to make in vivo DNA therapeutic protocols more effective. Results: Our preliminary work suggests that computational model might help in the definition of innovative therapeutic protocol, thanks to the fine tuning of all the involved operations. Conclusions: This approach is particularly interesting in optimizing complex and costly protocols for which the number of degrees of freedom prevents a experimental test of the possible configuration.

Gene therapy is a promising approach for treating a wide range of human pathologies such as genetic disorders as well as diseases acquired over time. Viral and non-viral vectors are used to convey sequences of genes that can be expressed for therapeutic purposes. Plasmid DNA is receiving considerable attention for intramuscular gene transfer due to its safety, simplicity and low cost of production. Nevertheless, strategies to improve DNA uptake into the nucleus of cells for its expression are required. Cytoskeleton plays an important role in the intracellular trafficking. The mechanism regulating this process must be elucidated. Here, we propose a new methodological approach based on the coupling of biology assays and predictive mathematical models, in order to clarify the mechanism of the DNA uptake and its expression into the cells. Once these processes are better clarified, we will be able to propose more efficient therapeutic gene transfer protocols for the treatment of human patients.