UCLA researchers led by Professor Feng Guo have developed a next-generation platform for designing antisense oligonucleotide (ASO) therapeutics using RNA structure as a blueprint, achieving enhanced specificity, efficacy, and versatility for the treatment of a wide spectrum of genetic and infectious diseases.
INNOVATION: UCLA researchers in the Department of Biological Chemistry have developed a transformative approach to the development of antisense oligonucleotide (ASO) drugs by leveraging structure-based design principles. Unlike traditional ASOs, which typically rely solely on Watson-Crick base pairing to bind linear RNA sequences, the patented method takes into account the complex three-dimensional structure of target RNAs, enabling much more selective and powerful therapeutic targeting.
Innovative Design Principle: The technology introduces a structural biology-driven strategy, called three-dimensional antisense oligonucleotides (3D-ASOs). These ASOs are designed to recognize and bind not only nucleotide sequences, but also the spatial arrangement and tertiary interactions of folded RNAs, such as hairpin loops, pseudoknots, and other structural motifs.
Enhanced Targeting and Potency: By accounting for RNA’s natural structural barriers, 3D-ASOs can optimize binding affinity, specificity, and therapeutic efficiency, leading to improved inhibition of target RNA molecules and lower risk of off-target effects. This is especially relevant for targeting structured and highly regulated RNA regions in diseases such as viral infections or genetic conditions.
Backbone and Chemotype Modifications: The patent outlines the compatibility of the structural targeting approach with various ASO chemotypes, such as locked nucleic acid (LNA), 2'-O-methyl, phosphorothioate, and morpholino modifications, which can further improve stability, cellular uptake, and pharmacokinetics while enhancing 3D interaction potential.
Validated Applications: The method has demonstrated robust efficacy by generating lead ASOs that inhibit replication of SARS-CoV-2, outperforming conventional designs by targeting unique RNA motifs like the transcription regulatory sequence and frameshift stimulation element.
Greater Selectivity: Structure-based ASOs offer superior discrimination between target and nontarget RNAs, dramatically reducing side effects.
Therapeutic Reach: Allows access to disease-relevant RNA sequences that have previously been elusive due to intricate folding and protein decoration.
Precision Medicine: Can be tailored for rare diseases (N-of-1 therapies) and rapidly adapted to emerging threats like novel viral pathogens.
Scalability: The approach facilitates high-throughput screening and rational optimization, accelerating development from lead identification to clinical candidate selection.