ABSTRACT
The COVID-pandemic has contributed to more than 5 million deaths worldwide in the last two years. Co-morbid conditions such as Type 2 Diabetes (T2D) , HTN, obesity, and CKD have been associated with increased mortality with COVID-19. In a large meta-analysis, the relative risk of mortality was 1.54 for patients with T2D and COVID-19. Thus, there is an imperative need to develop a platform for rapid and reliable drug screening/selection against COVID-related morbidity/mortality in T2D patients. With limited translatability of in vitro and small animal models to humans, human organ-on-a-chip models are an attractive platform to model in vivo disease conditions and test potential therapeutics. We seeded T2D or nondiabetes patient-derived macrophage and human liver sinusoidal endothelial cells along with normal hepatocytes and kupffer cells in the liver-on-a-chip (LAMPS - Liver Acinus MicroPhysiological System) developed by our group, perfused with media mimicking normal fasting or late metabolic syndrome (LMS - high levels of glucose, fatty acids, insulin, glucagon) states. We transduced both macrophage and endothelial cells to overexpress the SARS-CoV2-S (spike) protein and compared it with a control lentivirus transduction. We found that T2D cells overexpressing S-protein in LMS media (T2D chip) displayed an increased secretion of inflammatory cytokines compared to the nondiabetes chip over days. We then tested the effect of Tocilizumab (IL6-receptor antagonist) in T2D chips. Compared to vehicle control, Tocilizumab significantly decreased the S-protein induced inflammatory cytokine secretion in T2D chips but not in nondiabetes chips, indicating its higher efficacy in severe disease states only. This is consistent with what was observed in large clinical trials providing confirmatory evidence that the LAMPS T2D and nondiabetes chips serve as a relevant in vitro model system to replicate human in vivo pathophysiology of COVID and for screening potential therapeutics.
ABSTRACT
Adenovirus vectors are the most frequently used agents for gene therapy, including oncolytic therapy and vaccine development. It's hard to overestimate the value of adenoviruses during the COVID-19 pandemic as to date four out of four approved viral vector-based SARS-CoV-2 vaccines are developed on adenovirus platform. The vast majority of adenoviral vectors are based on the most studied human adenovirus type 5 (HAdV-C5), however, its immunogenicity often hampers the clinical translation of HAdV-C5 vectors. The search of less seroprevalent adenovirus types led to another species C adenovirus, Adenovirus type 6 (HAdV-C6). HAdV-C6 possesses high oncolytic efficacy against multiple cancer types and remarkable ability to induce the immune response towards carrying antigens. Being genetically very close to HAdV-C5, HAdV-C6 differs from HAdV-C5 in structure of the most abundant capsid protein, hexon. This leads to the ability of HAdV-C6 to evade the uptake by Kupffer cells as well as to distinct opsonization by immunoglobulins and other blood proteins, influencing the overall biodistribution of HAdV-C6 after systemic administration. This review describes the structural features of HAdV-C6, its interaction with liver cells and blood factors, summarizes the previous experiences using HAdV-C6, and provides the rationale behind the use of HAdV-C6 for vaccine and anticancer drugs developments.