DC6: Design of Novel Lipid-Based Targeting Ligands for Enhanced Oligonucleotide Delivery to Cardiac Tissue in Cardiomyopathy

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Supervisor: Prof.  S. Andersson 

Host Institute: AstraZeneca, Gothenburg (www.astrazeneca.com)

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Secondments planned: Radboud University Medical Center, The Netherlands; Karolinksa Institute, Sweden

 

Doctoral program: PhD program of Karolinska Institute

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Anticipated starting date: September 1st, 2025

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Project description:

Oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), are emerging medicines to treat diseases with unmet medical needs. However, they are highly anionic large molecules, preventing them from penetrating cell membranes via passive diffusion like small molecule drugs. Therefore, to use oligonucleotides as medicines, strategies to improve their cellular uptake and delivery to specific tissues are needed. Direct conjugation of oligonucleotides with ligands has shown great promise in efficiently delivering oligonucleotides. While GalNAc ligands have proven effective for delivering oligonucleotides to the liver, leading to several clinical candidate drugs, the development of ligands capable of targeting other organs has seen limited success. This project aims to address this delivery challenge by designing various lipid-based targeting ligands for efficient delivery of oligonucleotides to cardiac tissue. Diverse lipid-based siRNA conjugates will be synthesized and evaluated in vitro to assess their cellular uptake, efficiency, and toxicity. Promising candidates will be further assessed in relevant cardiac cell lines and in vivo in rodent models to gain insights into translational aspects, pharmacokinetics/pharmacodynamics (PK/PD), and duration of action. Additionally, we aim to map how lipid structure impacts the biodistribution of oligonucleotides and influences the therapeutic window. DC6 will have the opportunity to collaborate with biologists to evaluate the most promising lipid conjugates in relevant disease models.