Sirnaomics has developed a proprietary GalNAc-RNAi therapeutic platform, GalAhead, comprising two key technological components – mxRNA (miniaturized RNAi triggers) and muRNA (multi-unit RNAi triggers). mxRNAs are composed of single ~30 nt long oligonucleotides to downregulate individual genes, while muRNA molecules are comprised of multiple oligonucleotides (2 or more) to simultaneously silence two or more targets. We will present data validating these two technologies both in vivo and in vitro, as well as a progress report on quickly expending GalAhead therapeutic pipeline.

Human miRNAs have the potential to be versatile agents for regulating gene expression. Connecting a miRNA first to recognition of mRNA sequences and then to control of specific cellular functions is more difficult than has been widely assumed, slowing therapeutic applications. Here I describe approaches to find out when and where miRNAs are most likely to play important roles in disease.

Here we describe our work developing nanoformulations for RNA therapy and genome editing. Libraries of degradable polymers and lipid-like materials have been synthesized, formulated, and screened for their ability to deliver RNA payloads inside cells. These nanoformulations facilitate in vivo delivery to a range of tissues and can enable targeted gene suppression with siRNA, gene expression with mRNA, or even permanent genetic editing using the CRISPR/Cas9 system.

At Intellia, we are building a full-spectrum genome editing company. We are deploying the industry’s broadest and deepest toolbox, including novel editing and delivery solutions, to harness the immense power of CRISPR-based technologies for in vivo and ex vivo therapeutic applications, each with the potential to revolutionize the future of medicine. In this presentation, we will share the advances in the therapeutic application of CRISPR/Cas9 for genome editing.

The promise of oligonucleotide therapeutics is to use Watson-Crick-Franklin base-pairing rules to design drugs directly and rationally based on genomic information. Until recently, that promise has remained elusive because of cell barriers to oligonucleotide uptake. Receptor-mediated uptake through bioconjugation oligonucleotides has changed that. Avidity’s AOC technology uses monoclonal antibodies to cell surface proteins that are internalized in order to facilitate the functional delivery of oligonucleotide therapeutics into a broad range of cell and tissue types. 

In this talk, we will describe work in two diseases of unmet need in the brain, with the theme of using ASOs to correct disease-induced defects in RNA processing.  First, we describe an ASO to treat sporadic ALS by correcting mis-splicing of Stathmin2 that results from TDP-43-pathology.  We also describe ASO-induced redirection of RNA processing as a potential therapeutic for a common cause of inherited intellectual disability, Fragile X Syndrome. 

Currently underway are more than 20 biological studies focused on the use of thiomorpholino oligonucleotides (TMOs) as a therapeutic drug for the treatment of various genetic diseases. These collaborations are being carried out with cells in culture and several have progressed to studies in mouse models. Without exception, TMOs are more active than any other analogue tested and, in one case, a TMO is active under conditions where the 2'-MOE analogue is toxic to mice in the same treatment group.

For siRNAs, chemical modifications are necessary to regulate metabolic stability, potency (through effects on the interaction with the Ago2 enzyme and the targeted mRNA strand), and safety (impacted by metabolites and on-target specificity). We have evaluated numerous chemical modifications beyond the standard 2’-O-methyl, 2’-fluoro, and phosphorothioate linkages. These include backbone chiral phosphorothioates, glycol nucleic acids, altriol nucleic acids, gem 2′-deoxy-2′-α-F-2′-β-C-methyl, 5’-morpholino, and amino-oxy click chemistry (AOCC) mediated conjugates. Furthermore, novel spatial architectures like circular siRNAs have also been evaluated. This presentation will summarize how chemistry has made possible the currently exciting world of RNAi therapeutics.

The safety and efficacy of mRNA-based vaccines was evidenced during the COVID-19 pandemic: less than one year after the publication of the sequence of SARS-CoV-2, mRNA vaccines against COVID-19 were approved. More mRNA vaccines (against infectious diseases and cancer) are in clinical developments and are expected to be approved in the coming years. New mRNA formats (circular, replicating) and formulations (lipoplexes and polyplexes) are also being tested to further improve mRNA vaccines. I will present the past, present and future of mRNA vaccines.