Abstract
Gene-based approaches for protein replacement therapies have the potential to reduce the number of administrations. Our previous work demonstrated that expression could be enhanced and/or the applied voltage reduced by preheating the tissue prior to pulse administration. In the current study, we utilized our 16-pin multi-electrode array (MEA) and incorporated nine optical fibers, connected to an infrared laser, between each set of four electrodes to heat the tissue to 43 °C. For proof of principle, a guinea pig model was used to test delivery of reporter genes. We observed that when the skin was preheated, it was possible to achieve the same expression levels as gene electrotransfer without preheating, but with a 23% reduction of applied voltage or a 50% reduction of pulse number. With respect to expression distribution, preheating allowed for delivery to the deep dermis and muscle. This suggested that this cutaneous delivery approach has the potential to achieve expression in the systemic circulation, thus this protocol was repeated using a plasmid encoding Human Factor IX. Elevated Factor IX serum protein levels were detected by ELISA up to 100 days post gene delivery. Further work will involve optimizing protein levels and scalability in an effort to reduce application frequency.
Highlights
Gene electrotransfer (GET) holds great promise for the delivery of therapeutic agents.A number of clinical trials have shown positive results for gene-based therapies or vaccines [1,2,3,4,5,6,7,8]
We have previously shown the efficacy of a non-invasive multi-electrode array (MEA) for gene electrotransfer to the skin that utilizes a short gap between electrodes [20,33,34,35,36]
We previously demonstrated the minimally-invasive delivery of Factor IX using the MEA, where the bulk expression was confined to the skin with a small portion reaching adeno-associated virus (AAV) has progressed the furthest of the FIX replacement approaches that have been tested [51,54,55]
Summary
Gene electrotransfer (GET) holds great promise for the delivery of therapeutic agents.A number of clinical trials have shown positive results for gene-based therapies or vaccines [1,2,3,4,5,6,7,8]. The presence of antigen presenting cells has made the skin an excellent target for the delivery of DNA vaccines [20,21,22,23,24,25,26,27,28]. Due to the presence of capillaries present in the dermal layer [29], skin can be an excellent target for gene therapies that seek to enhance protein levels within the blood circulation or potentially target distant organs [30,31,32]. In order to penetrate the stratum corneum, cutaneous GET requires electric pulse conditions, including applied voltage or pulse number, that can result in discomfort or tissue damage. A minimally invasive method that does not require the use of high electric
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