RESEARCH ABSTRACT
Liver as the metabolic center, immune tissue, and drug factory for the production and delivery of Biologics
Liver is vital for the survival of the organism due to its critical roles in nutrition, detoxification of xenobiotics and metabolic wastes, and immune function. Due to their essential roles in anti-inflammation as well as liver and lung protection, glucocorticoids (GCs) are widely used to treat liver and lung diseases. In addition to direct beneficial effects on lung health, GCs act on the liver to maintain metabolic homeostasis and promote hepatic production and secretion of certain acute phase proteins that are important for lung health. Alcoholic liver disease (ALD) is a major cause of death worldwide. Alcoholic hepatitis is a severe form of ALD with high mortality that features jaundice, steatohepatitis, and cholestatic liver injury. GCs are currently the only drugs for sAH, with limited efficacy. Patients with severe alcoholic hepatitis (sAH) are highly susceptible to sepsis. Indeed, sepsis is a leading cause of death in sAH patients. GCs are also frequently used to treat sepsis, with demonstrated efficacy on liver failure and septic shock but controversial effects on the survival of septic patients. How to enhance GCs’ beneficial effects and avoid GCs’ side effects on other tissues, such as neuromuscular and bone, remains challenging. A major research interest of my laboratory is to understand the mechanisms of GC actions and develop novel targeted GC therapies for inflammatory liver diseases, acute respiratory distress syndrome (ARDS), and sepsis.
Liver-specific delivery of GCs will markedly improve the current GC therapy of liver diseases. By collaborating with Dr. Juntao Luo, a medicinal chemist in our department, we have developed novel liver-targeting GC prodrugs for the treatment of sAH and sepsis. Non-responsiveness to GC therapy is a major challenge in the clinics. GCs act via glucocorticoid receptor (GR) to exert their biological activities. Literature suggest that decreases of hepatic GR proteins and DNA-binding activities of GR are important mechanisms of GC non-responsiveness/resistance in sAH and sepsis. We have identified a novel non-phosphorable modification of GR with enhanced biological activities. We are developing super-active GR variants to overcome GC resistance. Tissue-specific mRNA delivery mediated by lipid nanoparticles (LNP) is a very promising therapeutic approach for various diseases. We are collaborating closely with Dr. Yamin Li, a medicinal chemist with extensive expertise at LNP-based mRNA/drug delivery to develop innovative LNP-based approaches of liver-specific and liver-lung-dual-specific mRNA delivery of fortified GR as novel therapeutics to overcome GC resistance in sAH, ARDS, and sepsis.
Compared to small molecule drugs, Biologics (proteins/peptides) have been gaining favor in recent years due to their more predictable therapeutic efficacy and less side effects. However, the much higher cost of production and short half-life of certain Biologics are the major limiting factors for the utilization of Biologics as therapeutics. Liver produces and secrets a large number of proteins such as albumin and acute phase proteins which have important roles in modulating inflammatory and anti-infectious responses. The recent successful preclinical and clinical studies have provided the key proof of concept regarding utilizing liver as the drug factory for the in vivo production and delivery of Biologics via LNP-mediated mRNA delivery. In addition to the delivery of GR mRNAs, we will codeliver mRNAs encoding antimicrobial peptides and/or antibodies for the treatment of sepsis and other liver/lung diseases. The long-term goal is to collaborate with medicinal chemists to combine bioengineering and chemical engineering to develop tissue-specific mRNA and drug delivery to 1) protect against liver and lung injury in sAH, ARDS, and sepsis, and 2) utilize liver as the drug factory for novel efficient and cost-effective production and delivery of Biologics.
