The presentation will describe the generation and the use of protein-based nano-capsules to deliver therapeutic RNAs to the brain for the treatment of CNS diseases. This delivery approach is making use of the brain tropism of a capsid protein derived from the John Cunningham virus. The therapeutic potential of this drug delivery system will be illustrated by mRNA-based enzyme replacement to repair the genetic defect in metachromatic leukodystrophy, a monogenetic CNS lysosomal storage disorder.

Advancing the frontier of RNA therapeutics demands innovative solutions for the precise, cell-selective delivery of nucleic acids-a challenge that has hindered progress for years. Notably, while liver-selective delivery has been achieved through GalNAc conjugation, extending this success to other tissues remains a formidable obstacle. Here, we introduce DELiveri, a massively-parallel, hypothesis-free screening platform designed to discover novel delivery conjugates, coupled with state-of-the-art AI models to predict productive delivery. We successfully utilized the DELiveri platform to screen ~84,000 small molecule conjugates in several cell types including primary cells and cancer cells. 

In this presentation, I will detail the journey of NeoVac Ltd., a clinical-stage, Oxford-based company from an academic idea to the clinic with chemistry, formulation, analytics, biology, regulation, and clinical team-and how we generated the first UK mRNA-LNPs vaccine platform manufactured and clinically tested in the UK. I will also detail the mRNA-LNPs therapeutic platform with preclinical data in inflammatory bowel diseases and in cancer.

Delivered mRNA vaccines benefit from a high antigen yield to stimulate an effective immune response. Translational output is one mode of regulation that can be engineered to further optimize antigen yield; however, the degree to which translational control is specified by mRNA sequence is poorly understood. Here, we collected a compendium of 2,894 mammalian ribosomal profiling datasets, distilling them into a transcriptome-wide atlas of translation efficiency measurements. We developed RiboNN to demonstrate that sequence-encoded mRNA features were sufficient to strongly predict translation efficiency. We propose RiboNN as a tool to guide the design of translation-optimized mRNA therapeutics for mRNA-based vaccines.

RNA activation with small activating RNAs can lead to upregulation of transcription in the nucleus resulting in increased mRNA and targeted protein. Such activation is specific and can last about a month This can be applied to many genes down regulated in common conditions such as cancer as well as rare genetic diseases such as sickle cell disease. Bio-distribution can be performed either with a universal or more targeted delivery approach. Wide bio-distribution is suitable in rare genetic diseases as well as with diseases related to the dark genome where the reduced long noncoding RNA is tissue, cell, and status specific.

We have developed a platform in which we design RNA-encoded programmable genetic “circuits” that detect molecular cues in a cell to specifically express a payload protein in cells that exhibit a particular molecular signature. We applied this platform to the development of our program which entails systemic delivery of lipid nanoparticle (LNP)-encapsulated mRNA-bearing programmable genetic circuitry that selectively expresses a therapeutic payload within target cells.

A CpG-A DNA TLR9 agonist in a virus-like particle, vidutolimod, induces systemic tumor regression as a monotherapy in PD-1 refractory advance melanoma, which is associated with the secretion of IFN-a.  We have now developed native backbone GU-rich RNA TLR7/8 agonists formulated in lipid nanoparticles that are stronger inducers of IFN-a secretion compared to CpG-A DNA, and which show synergy when used in combination. IV delivery of TLR7/8/9 agonists is well tolerated in mice and nonhuman primates, and induces pharmacodynamic biomarkers associated with human clinical response. Plans for clinical development will be discussed.

Eleven Tx develops a modality called xRNA, which is a synthetic mRNA that utilizes precisely positioned, non-canonical building blocks to resist degradation, increase protein production, and minimize immunogenicity. The outcome is a robust and long-lasting therapeutic effect. A proprietary high-throughput platform facilitates systematic screening of xRNAs and derivation of AI-enabled Structure-Activity-Relationships (SARs). Our hit optimization pipeline of screening, in vitro confirmation, and in vivo validation demonstrated broad utility.

mRNA therapeutics is rapidly emerging as a groundbreaking strategy for treating cardiovascular diseases (CVD), which claimed 20 million lives globally in 2022 and affects 650 million people. Despite advances in medicine, the need for curative therapies remains urgent. In my presentation, I will share a decade of work on mRNA therapies that promote cardiac regeneration, and combat fibrosis, cell death, and hypertrophy in CVD models. Additionally, we introduce novel cell-specific mRNA expression platforms, advancing the field of CVD therapeutics.

An ounce of prevention is worth a pound of purification. Using a fully immobilized polymerase-DNA scalable platform, we generate RNA that is free of dsRNA, DNA, and enzymes, eliminating the three purifications required in traditional manufacturing. DNA and enzymes remain active for very long production runs, further reducing costs. dsRNA levels, at synthesis, are far lower than can be achieved by downstream purification, enabling sensitive RNA applications.