Guest Speaker - 

Xiaobo Zhong, PhD, from the University of Connecticut 

Discussion - 

Impacts on Efficacy and Toxicity of ASO and siRNA Drugs by Intracellular Levels of Glucose, Fatty Acids, and Cholesterol

Abstract - 

Oligonucleotide therapeutics, including antisense oligonucleotide (ASO) and small interfering RNA (siRNA) therapeutics, have emerged as transformative modalities for treating rare genetic and common metabolic disorders. Despite advancements in delivery strategies, such as lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc) conjugates, their clinical efficacy and toxicity remain constrained by variable intracellular environments. Among key physiological modulators, glucose, fatty acids, and cholesterol profoundly influence clinical efficacy and toxicity of ASO and siRNA drugs. The seminar will present recent data from our lab by using in vitro hepatic cell models to illustrating how glucose, fatty acids, and cholesterol affect uptake, intracellular trafficking, and pharmacological outcomes of oligonucleotide drugs. Collectively, these metabolic factors not only shape drug efficacy but also modulate toxicity profiles, including hepatotoxicity, immune activation, and off-target gene silencing. Understanding the interplay between metabolic conditions and oligonucleotide pharmacology is therefore critical for optimizing therapeutic design and dosing strategies. Integrating metabolic biomarkers into preclinical and clinical evaluations could refine patient stratification, predict variability in drug response, and mitigate adverse effects. Future directions will be discussed with focus on mechanistic studies linking metabolic alterations to delivery bottlenecks and therapeutic outcomes, enabling the development of next-generation ASO and siRNA therapies with improved safety and efficacy across diverse patient populations.

Attendance Options - 

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