Orna has developed a highly efficient circularization process for generating large quantities of purified circular RNA (oRNA). We demonstrate, in the absence of modified nucleotides, that oRNA is immunoquiescent via in vitro and in vivo assessment. We present case studies using novel ionizable lipids for the generation of lipid nanoparticles to systemically deliver oRNA therapies for oncology (in situ CAR) and protein replacement.

Gene regulation, in health and disease, is mediated by the epigenetic modification to tune gene expression in a cell state-specific manner. Omega Therapeutics is developing programmable epigenetic mRNA therapeutics through an innovative platform capable of precisely and durably modifying chromatin state to treat disease. Based on a computationally guided, modular, and engineered approach, our epigenetic medicines can tune-expression one or many targets with high likelihood of translational success.

Small activating RNAs (saRNA) are double-stranded 21 nucleotide RNA that either target promoters or enhance genes leading to mRNA upregulation. MTL-CEBPA is an investigative drug that resulted from the conjugation of saRNA CEBPA with NOV 340 liposomes that target tumor-associated macrophages in order to alter favorably the tumor microenvironment. MTL-CEBPA has been administered safely in over 100 patients with advanced cancer and improved clinical outcomes in a subset of patients when co-administered with TKI or checkpoint inhibitors. 

We developed self-amplifying RNA and modified RNA platforms into vectors capable of carrying synthetic circuitry payloads that can provide a variety of desirable dynamics. Utilizing natural and synthetic RNA-binding proteins (RBPs), we constructed a toolbox capable of regulating expression via non-degradative, reversible binding to transcripts expressing therapeutic proteins of interest. We also encoded miRNA target sites on our RNA vectors to provide for highly specific cell type classification. We are using this technology to create next-generation cancer immunotherapy RNA vectors capable of activating therapeutic payloads discriminately in cancer cells.

I will introduce messenger-oligonucleotide conjugated RNAs (mocRNAs) to enable site-specific, robust, and modularized encoding of chemical modifications for highly-efficient and stable protein expression. By directly linking enzymatic and organic synthesis of mRNA, we envision that the mocRNA design will open new avenues to expand the chemical space and translational capacity of RNA-based vectors in basic research and therapeutic applications.

The development of nucleic acid therapeutics to both generate therapeutic proteins (via mRNA, pDNA) and silence proteins (via siRNA, miRNA, antisense oligonucleotides (ASOs)) and the development of gene editing technologies (CRISPR-Cas, TALENs, zinc finger nucleases) have opened new opportunities to precisely edit the genome and potentially enable one-time cures of genetic diseases. However, these therapeutics must overcome numerous obstacles to be successful, including rapid in vivo degradation, poor uptake into target cells, required nuclear entry, and potential in vivo toxicity in healthy cells and tissues. In this talk, I will discuss our efforts towards the development of new lipid nanoparticles (LNPs) that enable the delivery of nucleic acid therapeutics to target cells and tissues in vivo. Furthermore, I will describe new therapeutic strategies utilizing these LNPs for (i) mRNA CAR T cell engineering for cancer immunotherapy, and (ii) in utero mRNA delivery for treating disease before birth.

The presentation will introduce NEUWAY's protein-based nanocapsules as a scalable and versatile delivery technology for a broad range of therapeutic RNA applications. The use of these nanocapsules to deliver therapeutic mRNAs across the blood brain barrier will be described. The therapeutic potential of this delivery technology will be illustrated for the mRNA treatment of monogenetic CNS disorders such as metachromatic leukodytrophy (MLD).

Ischemic heart failure is a leading cause of mortality. This urgent unresolved medical need led scientists to evaluate whether induction of cardiac protection, post cardiac ischemic injury, can attenuate cardiomyocyte (CM) loss. In my talk, I will describe a minimal invasive method, using tail vain I.V injection to deliver therapeutic and protective modRNA directly to CM to attenuate CM cell death and improve the outcome post cardiac ischemic injury.

While immunotherapies have demonstrated striking responses in several hard to treat cancers, therapies do not work in all cancers and cures are not seen in all patients. Modified mRNA technology has been successfully applied in the development of vaccines, most recently against SARS-CoV-2 virus in the fight against COVID-19. I will present our application of mRNA therapies to develop novel immune-mediate therapies that activate the ability of the immune system to develop durable anti-tumor immunity with approaches ranging from encoding cancer vaccines against shared and personalized tumor antigens to different immunomodulatory proteins.