Gene Therapy for Acute Respiratory Distress Syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome that leads to acute respiratory failure and accounts for over 70,000 deaths per year in the United States alone, even prior to the COVID-19 pandemic. While its molecular details have been teased apart and its pathophysiology largely established over the past 30 years, relatively few pharmacological advances in treatment have been made based on this knowledge. Indeed, mortality remains very close to what it was 30 years ago. As an alternative to traditional pharmacological approaches, gene therapy offers a highly controlled and targeted strategy to treat the disease at the molecular level. Although there is no single gene or combination of genes responsible for ARDS, there are a number of genes that can be targeted for upregulation or downregulation that could alleviate many of the symptoms and address the underlying mechanisms of this syndrome. This review will focus on the pathophysiology of ARDS and how gene therapy has been used for prevention and treatment. Strategies for gene delivery to the lung, such as barriers encountered during gene transfer, specific classes of genes that have been targeted, and the outcomes of these approaches on ARDS pathogenesis and resolution will be discussed.

Sea Cucumber and Blueberry Extracts Suppress Inflammation and Reduce Acute Lung Injury through the Regulation of NF-κB/MAPK/JNK Signaling Pathway in Lipopolysaccharide-Treated C57BL/6 Mice

“…Even in patients who survive ALI, there is evidence that their long-term quality of life is adversely affected. The cellular characteristics of ALI include excessive transepithelial neutrophil migration into the alveolar and interstitial spaces, loss of alveolar-capillary membrane integrity, the release of pro-inflammatory and cytosolic mediators such as interleukin (IL-6), IL-1β, and tumor necrosis factor (TNF), and upregulation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways [11,12]. Several studies have shown that, following infection or injury to the lung tissues, plasma levels of pro-inflammatory cytokines can increase significantly (cytokine storm), leading to dysfunction and subsequent failure of multiple organs [13][14][15].…”

siRNA-Mediated Timp1 Silencing Inhibited the Inflammatory Phenotype during Acute Lung Injury

“…Alternative approaches in drug design and ALI/ARDS treatment are required. Gene-targeted strategies for ALI/ARDS cure primarily focus on alveolar fluid clearance (AFC), alveolar capillary barrier function (ACBF), and pulmonary inflammation [ 25 , 26 ]. Enhancing AFC and restoring ACBF implies gene delivery (e.g., Na + , K + -ATPase β1 subunit) [ 25 ], while targeting pulmonary inflammation can be carried out by both gene delivery and gene silencing.…”

“…Gene-targeted strategies for ALI/ARDS cure primarily focus on alveolar fluid clearance (AFC), alveolar capillary barrier function (ACBF), and pulmonary inflammation [ 25 , 26 ]. Enhancing AFC and restoring ACBF implies gene delivery (e.g., Na + , K + -ATPase β1 subunit) [ 25 ], while targeting pulmonary inflammation can be carried out by both gene delivery and gene silencing. The first strategy is to promote anti-inflammatory effects and implies the induction or delivery of anti-inflammatory cytokines, anti-oxidant enzymes, and other protective proteins, including IL10 [ 27 ], IL12 [ 28 ], superoxide dismutases (SODs) [ 29 ], heme oxygenase-1 (HO-1) [ 30 ], prostaglandins (PGs) synthase [ 31 , 32 ].…”

“…Neutrophil chemo-attractant Keratinocyte derived-chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) are good examples of proteins that have the potential for siRNA therapeutics validated in animal models [ 39 ]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is one of the most promising targets that serves as a central inflammatory mediator and regulates the expression of a number of downstream proinflammatory cytokines such as IL1b, IL6, and TNF-α, and sepsis-induced proinflammatory genes (iNOS, COX-2) [ 25 , 40 , 41 , 42 ]. Although NF-κB inhibition has been proved to be effective in suppressing inflammation in several studies [ 41 , 42 , 43 ], there are issues about the safety of the total inhibition of NF-κB because NF-κB is critical for maintaining normal immune responses [ 40 , 44 , 45 ].…”

Attenuation of the Severity of Acute Respiratory Distress Syndrome by Pomiferin through Blocking Inflammation and Oxidative Stress in an AKT/Foxo1 Pathway-Dependent Manner

“…Acute respiratory distress syndrome (ARDS) is a dangerous and life-threatening pathological condition which prevents enough oxygen from getting into the lungs and blood, serving as a serious and medical problem urgently needed solving [1]. In addition to bacterial and viral pneumonia, some nonpulmonary sources involving aspiration of gastric contents, severe trauma, drug reaction, and pancreatitis are all related with the development of ARDS [2][3][4]. The Berlin definition diagnostic criteria for ARDS involve arterial hypoxemia with PaO 2 /FiO 2 ratio < 300 mmHg and bilateral infiltrates without cardiogenic pulmonary edema on chest imaging [5].…”