Gene therapy technique offers a more targeted approach for treatment of pulmonary edema

Pulmonary edema, a life-threatening condition, occurs as excess fluid accumulates in the lungs, making it difficult to breath. Currently, no specific therapies exist to reverse its underlying cause. Instead, clinicians must rely on things like medications, monitoring and mechanical ventilation.

Previously, transient receptor potential vanilloid 4 (TRPV4), inhibitors of the mechanosensitive ion channel, were shown to inhibit development of pulmonary edema. However, these same ion channels are involved in many other physiological functions and can have effects in other areas of the body. A new study has developed and tested a method to directly target mechanical signaling mechanisms that activate TRPV4 in lung cells, which could avoid unwanted adverse effects on other tissues.

The researchers used adeno-associated virus vectors, relatively safe virus vectors similar to those used in clinical gene therapies, to deliver a gene encoding the protein CD98 HH in two types of human lung cells. This domain inhibits the pathway that leads to TRPV4 activation in response to physical cues.

To test the efficacy in a more complex biomimetic model, the study used a lung-on-a-chip device previously used to model normal lung functions as well as human pulmonary diseases, including pulmonary edema. The technique was successfully able to suppress pulmonary barrier leakage in the chip in response to mechanical stimuli, but not to chemical activators of the channel. The results suggest that this targeted approach could offer a new and more highly selective treatment of pulmonary edema in the future.

Source: “AAV-mediated gene therapy targeting TRPV4 mechanotransduction for inhibition of pulmonary vascular leakage,” by Juan Li, Amy M. Wen, Ratnakar Potla, Ezekiel Benshirim, Ariel Seebarran, Maximilian A. Benz, Olivier Y. F. Henry, Benjamin D. Matthews, Rachelle Prantil-Baun, Sarah E. Gilpin, Oren Levy, and Donald E. Ingber, APL Bioengineering (2019). The article can be accessed at https://doi.org/10.1063/1.5122967 .