Messenger RNA in lipid nanoparticles rescues HEK 293 cells from lipid-induced mitochondrial dysfunction as studied by real time pulse chase NMR, RTPC-NMR, spectroscopy.

Analytical tools to study cell physiology are critical for optimizing drug-host interactions. Real time pulse chase NMR spectroscopy, RTPC-NMR, was introduced to monitor the kinetics of metabolite production in HEK 293T cells treated with COVID-19 vaccine-like lipid nanoparticles, LNPs, with and without mRNA. Kinetic flux parameters were resolved for the incorporation of isotopic label into metabolites and clearance of labeled metabolites from the cells. Changes in the characteristic times for alanine production implicated mitochondrial dysfunction as a consequence of treating the cells with lipid nanoparticles, LNPs. Mitochondrial dysfunction was largely abated by inclusion of mRNA in the LNPs, the presence of which increased the size and uniformity of the LNPs. The methodology is applicable to all cultured cells.

A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis.

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.

Journey to a Receptor for Advanced Glycation End Products Connection in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: With Stops Along the Way in the Lung, Heart, Blood Vessels, and Adipose Tissue.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and the pandemic has yet to wane. Despite its associated significant morbidity and mortality, there are no definitive cures and no fully preventative measures to combat SARS-CoV-2. Hence, the urgency to identify the pathobiological mechanisms underlying increased risk for and the severity of SARS-CoV-2 infection is mounting. One contributing factor, the accumulation of damage-associated molecular pattern molecules, is a leading trigger for the activation of nuclear factor-kB and the IRF (interferon regulatory factors), such as IRF7. Activation of these pathways, particularly in the lung and other organs, such as the heart, contributes to a burst of cytokine release, which predisposes to significant tissue damage, loss of function, and mortality. The receptor for advanced glycation end products (RAGE) binds damage-associated molecular patterns is expressed in the lung and heart, and in priming organs, such as the blood vessels (in diabetes) and adipose tissue (in obesity), and transduces the pathological signals emitted by damage-associated molecular patterns. It is proposed that damage-associated molecular pattern-RAGE enrichment in these priming tissues, and in the lungs and heart during active infection, contributes to the widespread tissue damage induced by SARS-CoV-2. Accordingly, the RAGE axis might play seminal roles in and be a target for therapeutic intervention in SARS-CoV-2 infection.

COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients With Cardiovascular Disease.

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.