Sirnaomics has developed proprietary GalNAc-RNAi therapeutic platform – GalAhead, with mxRNA comprising one of its key technological components. mxRNAs (or miniaturized RNAi triggers) are composed of single 31-33 nt long oligonucleotides, demonstrating excellent activity in primary hepatocytes (in vitro) and in mice (in vivo). In addition to the experiments in vitro and with rodents, we will present results of our 13-week study in non-human primates conducted with the candidate molecule for our frontrunner GalAhead therapeutic program.

To address the unmet needs in treatment of liver disorders caused by overabundance of hepatocyte factors, OliX Pharmaceuticals has developed a N-acetyl galactosamine (GalNAc) conjugation platform for high-efficiency, ASGPR-mediated delivery of asiRNA compounds to hepatocytes. We have also established dynamic discovery and preclinical stage programs to target multiple hepatic disorders, among them, Nonalcoholic steatohepatitis (NASH) and HBV. Here we present the latest advancements in our liver programs.

Advancements in the chemical design of oligonucleotide drugs have improved potency, safety and duration leading to better clinical outcomes. Efforts to expand the boundaries of existing chemical space to further enhance the properties of RNA therapeutics will be presented.

Thiomorpholino oligonucleotides (TMOs) and their DNA chimeras are new analogues containing morpholino- and 2’-deoxyribonucleosides joined through thiophosphoramidate internucleotide linkages. The TMO and TMO/DNA chimeras were observed to have higher melting temperatures when compared to natural DNA/DNA and DNA/RNA duplexes and are active with RNase H1. These analogues are efficiently taken up by cells and stimulate biological activity in primary cells as well as various established cells lines. Current research underway in over 20 collaborations are focused primarily on rare and fatal genetic diseases. The lecture will focus on results from Duschenne Muscular Dystrophy, Niemann-Pick type C1 and regulating the maturation of TUG 1 and TERT RNA. 

RNA therapeutics have great potential to selectively treat human disease, especially cancer, COVID and neurological disorders.  However, due to their 8-14 kiloDalton size and 20-40 negatively charged phosphates, RNAs have limited (<1%) to no ability to overcome a billion years of evolutionary defenses that prevent RNAs from escaping across the endosomal lipid bilayer membrane into the cytoplasm of cells.  Consequently, endosomal escape remains The Technological Problem to solve for wide-spread development of RNA therapeutics. 

We have developed a novel oligonucleotide delivery platform by conjugation with Entrada’s proprietary Endosomal Escape Vehicle (EEV), a class of cyclic peptides designed to facilitate intracellular delivery and endosomal escape. The preclinical results have confirmed the significant therapeutic potential of the strategy for DMD and demonstrated that the EEV platform can serve as a general and highly efficient delivery technology for the extrahepatic delivery of therapeutic oligonucleotides.

BK virus (BKV) is a universal latent renal virus that reactivates in kidney transplantation patients and can lead to graft loss. No treatment exists for combatting BK virus. As such, treatment options for BKV are vital. At Hybridize, we have developed an innovative RNA-based direct-acting antiviral strategy that prevents BKV-mediated disease.

The benefits of immunotherapy are often limited by an immunosuppressive environment at the tumor site involving T-regulatory (Treg) and myeloid-derived suppressive cells. We developed self-delivering FANA antisense oligonucleotides (ASO) against human FOXP3 that were screened for their ability to knockdown FOXP3 and decrease human Treg suppressive function in vitro. Selected FANA were then tested in immunodeficient NSG mice reconstituted with human PBMC and shown to knockdown human FOXP3 in vivo. We also developed FANA ASO against murine Foxp3 that knocked-down Foxp3 mRNA and protein expression in vitro and in vivo, decreased Treg suppressive function and inhibited tumor growth in syngeneic lung tumor models. In summary, we have developed highly efficacious FANA ASO lead candidates that can knockdown FOXP3, inhibit Treg function and promote antitumor immunity and are proceeding with IND-enabling studies.

Multiple siRNA, ASOs, and now antibody-oligo conjugates (AOCs) have moved into the clinic, what will be next? Overview of synthesis chemistry from Dharmacon including methods for conjugation and complex modification patterns to support your research – from screening to scale up.

MicroRNAs are short non-coding RNAs that regulate biochemical pathways by RNA interference (RNAi). Dysregulation of microRNAs is associated with many diseases including fibrosis. The presentation shows the development of anti-fibrotic therapeutic strategies using anti-miRs as therapeutic molecules.

Mitotherapeutix has identified MCJ/DNAJC15, a novel negative regulator of mitochondrial metabolism, as a key target to treat NASH and other metabolic diseases. We have performed SAR and selected a lead GalNAc-MCJ siRNA as a clinical candidate for NASH. Treatment targets hepatocytes and effectively knocks down MCJ reducing disease severity in NASH models. Activity has been confirmed in non-human primates. Preclinical toxicology and PK/PD studies are planned to support an IND-filing.

BK virus (BKV) is a universal latent renal virus that reactivates in kidney transplantation patients and can lead to graft loss. No treatment exists for combatting BK virus. As such, treatment options for BKV are vital. At Hybridize, we have developed an innovative RNA-based direct-acting antiviral strategy that prevents BKV-mediated disease.