Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome

Abstract

In the 50 years since acute respiratory distress syndrome (ARDS) was first described, substantial progress has been made in identifying the risk factors for and the pathogenic contributors to the syndrome and in characterising the protein expression patterns in plasma and bronchoalveolar lavage fluid from patients with ARDS. Despite this effort, however, pharmacological options for ARDS remain scarce. Frequently cited reasons for this absence of specific drug therapies include the heterogeneity of patients with ARDS, the potential for a differential response to drugs, and the possibility that the wrong targets have been studied. Advances in applied biomolecular technology and bioinformatics have enabled breakthroughs for other complex traits, such as cardiovascular disease or asthma, particularly when a precision medicine paradigm, wherein a biomarker or gene expression pattern indicates a patient's likelihood of responding to a treatment, has been pursued. In this Review, we consider the biological and analytical techniques that could facilitate a precision medicine approach for ARDS.

Figure 1

Integrative approaches to identify and test new precision therapies for acute respiratory distress syndrome Observations made from candidate and discovery methods fuel traditional hypothesis testing and inform novel designs such as EVLP or lung-on-a-chip. Drug candidates with a consistent signal for benefit across multiple study designs are the most promising for biomarker-enriched clinical trials. EVLP=ex-vivo lung perfusion. CRISPR=clustered regularly interspaced short palindromic repeats. CAS9=CRISPR-associated protein 9.

Figure 2

Ex-vivo lung perfusion system Human lungs under the dome are ventilated and perfused.

Figure 3

Illustration of a microfabricated lung-on-a-chip The chip consists of a three-dimensional microchannel system with culture chambers for both epithelium and endothelium at a porous interface. The epithelium and endothelium are capable of being stretched and perfused.