Engineered Vectors and Virus-like Particles for Circular mRNA Expression

Background & Unmet Need

• mRNA is a promising therapeutic modality, but is limited by the relatively short half-life of mRNA in the cytoplasm
• Another major challenge of mRNA therapeutics is achieving delivery to specific cell types, as mRNAs are taken up primarily by the liver when administered systemically
• Circular mRNAs are a promising alternative to linear mRNAs due to their lower rate of degradation and increased duration of expression
• One emerging approach for delivering mRNAs to specific cell types is virus-like particles (VLPs), which comprise the structural proteins needed to assemble a viral capsid without viral genomic material
• Unmet Need: Improved methods for delivery of mRNA therapeutics with stable in vivo expression

Technology Overview

• The Technology: Optimized vectors and virus-like particles for high efficiency expression of circular mRNAs in mammalian cells
• The inventors have expanded their RNA expression system, Tornado, to generate mRNAs by using an internal ribosomal entry site (IRES)
• This system can be used as a VLP transfer plasmid to generate VLPs packaging a circular mRNA
• In their proof-of-concept construct, the VLP transfer plasmid encodes a fluorescent reporter system for circular mRNA-specific translation
• PoC Data: Experimental VLPs increased levels of protein expression, producing >5-fold luminescence than controls 24 hours after transduction
• Spike-pseudotyped VLPs demonstrated selective delivery into ACE-2-expressing cells, showing that experimental VLPs can achieve cell-type specificity

Technology Applications

• Enhanced delivery of mRNA for production of therapeutic proteins or antibodies
• Enhanced delivery of mRNA encoding viral or cancer antigens for vaccination
• Enhanced delivery of gene editing proteins like Cas or cell therapy constructs like chimeric antigen receptors (CARs)

Technology Advantages

• Vectors and VLPs with circular RNA maintain more stable expression than those with linear RNA
• Extended expression of viral or cancer antigens, CARs, or gene editing proteins could enhance immune response, target cell killing, or gene editing efficiency (respectively)
• Circular mRNAs packaged into VLPs can be directed to specific cell-types