Session 1. Nucleic Acids as Therapeutic Agents

The main objective of the Nucleic acid as Therapeutic Agents session is to give an overview of the setbacks and problems we have encountered in the RNA field and to show the hurdles we have faced and are facing to move forward with nucleic acid-based therapies. The cases of success and failure and how the field is emerging and what is yet to come, and most importantly what paths we need to take to flood the market with nucleic acid-based therapies and what strategies are being followed. It will also try to show how the different types of RNA-based molecules are therapeutic alternatives and what problems are encountered in each case.

OLIGOFASTX: The end-to-end shuttle for the development of oligonucleotide-based therapies for the treatment of rare diseases

OLIGOFASTX is a consortium that aims to create an industrial niche that gathers all the necessary capabilities and knowledge to favour the development of oligonucleotide-based therapies for rare diseases, accelerate and promote them definitively in Spain and Europe. This industrial consortium includes companies with high expertise in siRNAs, aptamers, anti-miRNAs, nucleic acid modelling, drug delivery systems and novel oligonucleotide synthesis strategies.

Living in the World of RNA Therapeutics

Synthetic small interfering RNAs (siRNAs) are potent inhibitors of gene expression; these agents act through the natural RNA interference (RNAi) mechanism using a biomimetic pathway. Our laboratory demonstrated the very first in vivo RNAi mediated silencing in mouse liver and jejunum in 2004. To deliver therapeutic siRNAs into human liver hepatocytes for therapy, we have further developed a three-pronged approach with the goals of enabling delivery to hepatocytes after both intravenous and subcutaneous administration. These methods include chemical modification of siRNAs, lipid nanoparticle (LNP) formulation of siRNAs, and multivalent N-acetylgalactosamine (GalNAc) conjugation of siRNAs.

This presentation will cover the molecular basis of approval of five RNAi drugs at Alnylam including the chemical modifications and chemical motifs used in each siRNA to ensure Argonaute2 (Ago2) recognition, silencing efficiency, metabolic stability, off-target mitigation, and safety. We will also present our current explorations of this platform driven by rational design of novel chemical modifications and motifs.

Aptamers as improved therapeutic tools: OLIGOFASTX consortium as a model of oligonucleotide-based drug development

Aptamers are single-stranded nucleic acids which bind with high affinity and specificity to a target molecule of interest and are selected in vitro from combinatorial populations using the SELEX method. Aptamer technology is an innovative alternative much less known than that of monoclonal antibodies with many outstanding advantages over them. This technology provides multiple applications in biotechnology, health, agriculture-food industry and other sectors. In this presentation, I will show AptusBiotech’s pipeline which is focused on researching novel antitumor therapies based on aptamer technology. Among them, I will highlight our participation in OLIGOFASTX consortium as a comprehensive platform for the sustainable development of oligonucleotide-based therapies

Preclinical development of an antimiR-based drug to treat Myotonic Dystrophy disease

Myotonic Dystrophy type 1 (DM1) is a chronically debilitating rare genetic disease that originates from an expansion of a non-coding CTG repeat in the DMPK gene. The expansion becomes pathogenic when DMPK transcripts contain 50 or more repetitions due to the sequestration of the muscleblind-like (MBNL) family of proteins. Depletion of MBNLs causes alterations in splicing patterns in transcripts that contribute to clinical symptoms such as myotonia and muscle weakness and wasting. We previously found that miR-23b directly regulates MBNL1 in DM1 myoblasts and mice and that antisense technology (“antimiRs”) blocking this miRNA boosts MBNL1 protein levels. We performed an in vitro screening looking for the most effective antimir-23b, in DM1 human myoblasts using naked oligos and oligos conjugated with different hydrophobic moieties. The most effective antimiR ATX-01 was further tested in vivo in a well-known mouse model of the disease. The in vitro and in vivo data obtained with ATX-01 confirmed that this new molecule was at least 10 times more efficacious at rescuing molecular and functional disease phenotypes. The pharmacokinetic and preliminary toxicity data that we have obtained during the last year in different species provide further evidence that miR-23b could be a valid therapeutic target for DM1, and that ATX-01 could be a potent therapeutic tool against DM1.

Organised by SDDN in collaboration with Fundacion Medina



CIF G18889444