Gene Therapy for ALI/ARDS

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by acute respiratory failure and are associated with diverse disorders, such as pulmonary edema, pneumonia, sepsis, trauma, shock and lung contusion. Gene therapy is a potentially powerful approach to treat a variety of diseases related to ALI/ARDS. Numerous viral and non-viral methods for gene delivery to the lung have been developed, although pulmonary architecture and immune activation represent barriers to successful gene transfer. In this review, recent advances in the development of more efficient viral and non-viral gene transfer systems are discussed. In addition, the current status of gene therapy applied to ALI/ARDS-associated pulmonary diseases is reviewed. With the development of more efficient gene therapy vectors, gene therapy is a promising strategy for clinical application in the not too distant future.

Electroporation-Mediated Gene Delivery of Na+,K+-ATPase, and ENaC Subunits to the Lung Attenuates Acute Respiratory Distress Syndrome in a Two-Hit Porcine Model

“…This may also indicate that the gene therapy did not decrease capillary permeability but did improve clearance of the edema fluid. Taken together, these data suggest that electroporation-mediated gene therapy may prove to be an important treatment and prevention therapy for the pulmonary edema associated with ARDS by enhancing alveolar epithelial function (9, 12). …”

“…Recent advances in the development of more efficient viral and non-viral methods for gene delivery have increased clinical application (12). Over the past two decades, numerous viral and non-viral approaches have been proposed and developed to transfer genes to the lung but all have serious limitations.…”

“…Unfortunately, to date, only limited successes have been made in clinical trials (12). Perhaps the major reason for this is that the majority of viral and non-viral vectors for gene delivery have serious drawbacks limiting efficacy, including inefficiency of gene transfer and immunological and inflammatory responses.…”

Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia

“…It has been proposed that transient genomic editing and manipulation of protein expression by gene therapy can potentially restore known altered aspects of lung biology that favor resolution of lung injury (21–23). However, in the injured lung, traditional viral techniques may worsen inflammation and could be neutralized by natural lung physical and immunological barriers that prevent such transfection(24).…”

“…The possible events of in vivo electroporation have been elegantly described elsewhere (25, 26). In the lung, however it does confer advantages over other gene therapy techniques, among these the lack of inflammation, as well as the lack of integration into the chromosome making transgene expression transient and short-lived, ideal for the resolution of acute lung injury without concern for long term effects or mutagenesis(21, 27). We have been successful in achieving high levels of expression both in naïve and injured lungs by using in vivo electroporation(22, 27–29).…”