• Secarna pioneers antisense research by characterization of multi-specific antisense oligonucleotides to identify factors that determine target gene knockdown
• Top factors identified to have an impact on ASOs’ activity include abundance of the target transcript, length of the transcript, binding site availability and number of binding sites
• The data offer great potential to improve the process of generating safe and efficient antisense-based drug candidates guided by an in-silico approach

Munich/Martinsried, Germany, August 05, 2021 – Secarna Pharmaceuticals GmbH & Co. KG (“Secarna”), a biopharmaceutical company focusing on the discovery and development of next generation antisense oligonucleotide (ASO) therapies to address challenging or previously undruggable targets via its LNAplus™ platform, announced today the publication of new scientific insights which have the potential to improve the in-silico process to design safe and efficient therapeutic locked nucleic acid (LNA)-modified ASOs. The article, “Investigation of the activity of antisense oligonucleotides targeting multiple genes by RNA sequencing” was published in Nucleic Acid Therapeutics was published in Nucleic Acid Therapeutics: https://www.liebertpub.com/doi/10.1089/nat.2020.0932

Standard ASO design is based on the sequence complementarity of the oligo to its target. However, the degree of target knockdown that ASOs can achieve varies strongly between different ASOs having full complementarity to the target. To determine which factors affect the ASOs’ activity, Secarna has used a novel approach: the Company has designed and screened 51 multi-specific ASOs with a common target (IDO1, a gene involved in tryptophan metabolism), and varying numbers of diverse other targets (up to approx. 2,500). In a first step, Secarna investigated the ASO’s effectivity against IDO1. Subsequently, the impact of nine selected ASOs on the overall gene expression profile was further investigated by RNA-sequencing. The resulting dataset formed the basis for the examination of the roles of different factors that may influence ASO activity, allowing Secarna to base their findings on an unpreceded database of thousands of genes.

In the research conducted, the top factors determined to have an impact were: abundance of the target transcript and copy variant, length of the transcript, binding site availability and number of binding sites. Secarna has observed that there is a significantly higher chance for target knockdown of long genes compared to short genes, for genes with high expression compared to those with lower expression and of those genes that have more than one binding site for the respective ASO. While the availability of the binding site is essential for the ASO’s activity, interestingly, the position of the binding site – either in the 5’ or 3’ portion of the transcript – does not play a significant role. Due to the nature of multi-specific ASOs, which target a large number of transcripts in a cell at the same time, Secarna was able to investigate the availability of RNase H as a limiting factor in overall knockdown activity. Surprisingly, within the experimental conditions, there were no obvious indications that availability of either RNAse H or ASO molecules at the site of action limit ASO activity.

The findings generated through the screening of multi-specific antisense oligonucleotides are the first of their kind and with this Secarna has described new key players in ASO knockdown effectivity and, at the same time, validated previously known factors.

“Antisense oligonucleotides are an emerging therapy option that aims to address previously undruggable targets. The design of these molecules is key to obtaining candidates with high activity and maximum specificity to reduce off-target effects, resulting in a safe therapy,” said Frank Jaschinski, PhD, CSO of Secarna Pharmaceuticals. “In our recent publication, we provide comprehensive knowledge on the different factors that affect the activity of ASOs which can improve the in-silico selection process. By using multi-specific ASOs as tool compounds, we have identified determinants for ASO activity that can be taken into consideration to improve the selection process of highly potent and selective ASOs in the future. With the implementation of this information into our proprietary Oligofyer™ platform, we expect not only to ensure an even more efficient selection process but also considerable cost and time savings.”

Alexander Gebauer, MD, PhD, CEO and Managing Director of Secarna Pharmaceuticals, added: “At Secarna, we are constantly working on improving our proprietary LNAplus™ ASO therapies platform. We are pioneering novel research approaches that will support us in further understanding the operating principles of ASOs to fulfill our ultimate mission: rapidly generate safe and efficient drug candidates to address challenging or previously undruggable targets. We are proud of our achievements and are excited to share them with the scientific community.”

About Secarna’s proprietary drug discovery platform, LNAplus™

For discovering, testing and selecting antisense oligonucleotides (ASOs) for pre-clinical and clinical development, Secarna employs its proprietary, customized LNAplus™ drug discovery platform. LNAplus™ encompasses all aspects of drug discovery and pre-clinical development and has proven to be fast, reliable, scalable, efficient and to provide for a uniquely integrated workflow, enabling the discovery of novel antisense-based therapies for challenging or currently undruggable targets. The platform includes the powerful proprietary Oligofyer™ bioinformatics pipeline, a streamlined, high efficiency screening process including our proprietary LNA-Vit(r)ox™ safety test system as well as target-specific functional assays. Secarna’s platform and ASOs have been validated by numerous in-house projects as well as in several academic and industry collaborations.

About Secarna Pharmaceuticals GmbH & Co. KG

Secarna Pharmaceuticals is the next generation antisense oligonucleotide (ASO) company addressing high unmet medical needs in the areas of immuno-oncology, immunology, as well as viral, inflammatory / fibrotic, neurodegenerative and cardiometabolic diseases. Secarna’s mission is to maximize the performance and output of its proprietary LNAplus™ antisense oligonucleotide discovery platform, as well as to develop highly specific, safe, and efficacious best-in-class antisense therapies for challenging or currently undruggable targets. With over 15 development programs focusing on targets in indications where antisense-based approaches have clear benefits over other therapeutic modalities, Secarna is the leading European antisense drug discovery and development company. www.secarna.com