At the DARTER COST Action, we want Antisense Oligonucleotides (ASOs) to reach their full potential as a therapeutic option through networking and capacity building. To achieve this end, the project is divided into four Working Groups (WGs). The first three WGs deal with scientific questions (current state-of-the-art, model systems and safety and toxicology studies of delivery systems), while the last WG focuses on capacity building (stakeholder dissemination).
WG1
Delivery strategies
The main objective of this WG is to create consensus and identify gaps in the current knowledge on the mechanisms that are involved in Antisense Oligonucleotides (ASOs) delivery and on the different approaches currently tested to optimise the process.
Leaders: Prof Camilla Foged, Dr Gulay Büyükköroğlu
This action includes the organisation of several meetings (a large kick off meeting, a final meeting, plus several specific workshops) and the publication of meeting reports. These reports are made available to DARTER Action’s members shortly after each meeting and edited for scientific journal publication.
The specific workshops focus on the mechanisms of delivery/cellular uptake, tissue delivery and routes of administration and are held in collaboration with members of other WGs.
WG2
Model systems
This WG aims to examine cell culture and animal models currently used in the development of ASOs from the perspective of their suitability to assess ASO delivery and the toxicity of delivery systems.
Leaders: Dr Alex Garanto, Dr Haiyan Zhou
After an initial meeting, the members of this WG draft guidelines and Standard Operating Procedures (SOPs) to include current models and recent developments, such as 3D cultures, organoids and tissue engineering techniques. To do this, outcome measures and delivery assessment workshops will be organised. The validated SOPs will be uploaded on DARTER’s website and any other interested network or scientific society’s webpage, so that they can be shared with the research community.
WG3
Safety and toxicology
This WG deals with an issue often overlooked until late stages of development. In pursuit of better delivery and higher cellular uptake, ASOs are being optimised and new chemistries developed or conjugated with various ligands. While these developments might lead to candidates with higher potency, it is important to keep the safety aspects in sight and screen for potential toxicity in early phases of preclinical development to avoid subsequent failure before it can reach the clinic.
Leaders: Dr Aurélie Goyenvalle, Dr Cecilia Jimenez
Around 75 members of our COST action on Delivery of Antisense RNA Therapeutics from more than 15 different countries and invited speakers met in Munich on October 11th and 12th 2019 to discuss model systems and safety and toxicology for RNA therapeutics. The meeting was organized by Alex Garanto (leader of WG2), Aurélie Goyenvalle (leader WG3) and Sabine Krause (local organizer). During this workshop, several speakers from both academic and private gave presentations about the use of antisense technology in specific disease models and how to assess the safety profile of antisense molecules.
For the program, use the following links: Munich Workshop WG2 & WG3 Program
The presentation of the Safety and toxicology session can be found here (insert link to presentations)
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Introduction lecture about ASO chemistries, PK and the different type of ASO-mediated toxicities. Patrik Andersson (AstraZeneca, Sweden)
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Identification of Proinflammatory ASOs: Lessons learned from thousands of ASO Dr. Padma Narayanan (Ionis Pharmaceuticals, Carlsbad, USA)
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ASO mediated complement activation / thrombocytopenia. Padma Narayanan (Ionis Pharmaceuticals, Carlsbad, USA)
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In vitro safety screening for liver and kidney toxicity: “In vitro Assays capturing toxicity risks” Sabine Sewing (Roche, Basel, Switzerland)
Histopathology analysis of liver and kidney: identification of typical lesions induced by ASO. Dr. Pierluigi Fant (Charles River, Lyon, France)
WG4
Stakeholder communication and dissemination
This WG is in charge of integrating social media into the dissemination with more traditional communication channels. The dissemination also includes explaining the scientific objectives of Darter Action as well as creating short explanatory videos to make the information accessible to patients and families.
Leaders: Prof Michela Alessandra, Dr Marisol Montolio, Dr Ana María Sanchez Perez
