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Overview

Read the conference report summarising the event (PDF).

This Royal Society meeting will seek to explore the opportunities and existing challenges of oligonucleotide-based therapies as a platform. Speakers will discuss overcoming barriers in manufacturing and stability of molecules, and the delivery, and efficacy and efficiency of oligonucleotide-based therapies. 

Background

This meeting will bring together key stakeholders from across the sector to highlight the emerging technologies in the field and explore opportunities around the use of oligonucleotides as therapeutic agents, including siRNA, antisense, and aptamers.  

Speakers will also outline some of the key challenges such as targeted delivery, the balance of efficacy and efficiency, and manufacturing that must be addressed if these wide ranging therapeutics are to be successful.

The conference will conclude with a panel discussion on the future of Oligonucleotide therapeutics.

About the conference series

Supported by AstraZeneca, the meeting will form part of the Royal Society’s Transforming our future conferences in the life sciences. These meetings are unique, high-level events that address the scientific and technical challenges of the next decade. Each conference features cutting edge science from industry and academia and brings together leading experts from the scientific community, including regulatory, charity and funding bodies.

Organisers

Schedule


Chair

13:05-13:25
Genetic Based Medicines for Neurological Diseases

Abstract

Currently there are multiple genetic based medicines being pursued for neurological diseases including antisense technology, gene therapy and gene editing technologies. Antisense oligonucleotides (ASOs are one of the more advanced technologies. ASOs are synthetic, chemical modified nucleic acid analogs designed to bind to RNA by Watson-Crick base paring. Upon binding to the RNA, ASOs modulate the function of the targeted RNA through a variety of mechanisms. Both protein coding, as well as non-coding RNAs, can be targets of ASO based drugs, significantly broadening therapeutic targets for drug discovery compared to small molecules and protein based therapeutics. The approval of nusinersen (Spinraza™) as a treatment for spinal muscular atrophy (SMA) validates the utility of antisense drugs for the treatment of motor neuron diseases. The application of antisense technology as potential therapy for other neurological diseases and neurodevelopmental disorders will be discussed.

Speakers

13:25-13:45
Basic science of Oligonucleotides and how chemistry can solve some of the challenges faced

Speakers

13:45-14:05
Challenges and opportunities in targeted delivery and distribution

Abstract

While oligonucleotide therapies have enormous therapeutic potential, significant challenges in drug delivery to many extra-hepatic cell/tissue types remain. This is particularly the case for neurological and neuromuscular disorders where limited efficacy and poor oligonucleotide delivery to affected tissues including skeletal muscle, cardiac muscle and the central nervous system, represent both major challenges and opportunities. A wide range of delivery technologies are being advanced to address this challenge, including bio-conjugates and nanotechnologies. Current progress and future prospects will be discussed.

Speakers

14:05-14:25
Panel Q&A

Speakers

14:35-14:50
Exploring the safety of antisense oligonucleotides

Abstract

There is an urgent need for increased mechanistic understanding of the events that follow entry of ASOs into cells. One area that has been little explored is the effect that ASOs have on the RNA binding proteome (RBPome). The RBPs have key regulatory functions and post-transcriptional networks are combinatorially controlled by common RBPs, which regulate gene expression via coordination of RNA splicing, mRNA export, stability, localization and translation to maintain homeostasis. In addition, many the ~1000 proteins that have the capacity to bind RNA, are multifunctional, with their activities controlled through RNA binding. Subverting normal cellular RBP function through their interaction with ASOs could have cell-wide impact on: i) key metabolic functions such as the liver in appropriate binding of ASOs to RNA-binding metabolic enzymes could subvert this key regulatory step; ii) cytoplasmic control of gene expression e.g. by competing with endogenous RNA turnover mechanism; iii) the localisation of RNA binding proteins; iv) the response to cell stress e.g. viral infection. We have developed in vitro models capturing cytotoxicity and proinflammatory ASO effects and established detailed in vitro and in vivo safety profiles for a set of reference ASOs. Preliminary data using orthogonal organic phase separation (OOPS) indicate that we can identify differences in RBP binding between ASOs of different properties. By building on our findings from hepatocyte delivery of GalNAc conjugated ASOs and siRNA and using the same set of ASOs for different cell biological/ biochemical assays across selected cell-types, we are generating a large knowledge base to identify desired and undesired properties and mechanisms for efficient and safe uptake of ASOs. In the future these data will be key for optimizing novel delivery approaches, translational and quantitative risk assessment strategies and guide optimization of novel delivery systems from both efficacy and safety perspective. 

Speakers

14:50-15:05
Living in the World of RNA Therapeutics

Abstract

Synthetic small interfering RNAs (siRNAs) are potent inhibitors of gene expression; these agents act through the natural RNA interference (RNAi) pathway. After the demonstration of twenty years of mammalian RNAi in cells, four drugs impacting patients globally that act through the RNAi pathway have been approved.  To deliver therapeutic siRNAs into liver hepatocytes, Alnylam has developed a three-pronged approach involving chemical modification of siRNAs, lipid nanoparticle (LNP) formulation of siRNAs for intravenous administration, and trivalent N-acetylgalactosamine (GalNAc) conjugation to siRNAs for subcutaneous administration. 

The LNP strategy with a partially chemically modified siRNA resulted in the first RNAi therapeutic, ONPATTRO®(patisiran), approved in 2018 is used to treat polyneuropathy in patients with hereditary ATTR amyloidosis.  The approval of ONPATTRO paved the way for a whole new class of RNA-based medicines and further validated LNP platform-based delivery of nucleic acids for human therapeutics including mRNA-based vaccines. 

In 2019 the human therapeutic utility of the the asialoglycoprotein (ASGPR) receptor-GalNAc ligand pair for delivery of nucleic acids for the first-time was fully realized by Alnylam. By combining the chemical modifications of oligonucleotides contributing to various flavors of Enhanced Stabilization Chemistry (ESC, Advanced ESC and ESC+) along with the triantennary N-acetylgalactosamine (GalNAc) ligand, Alnylam enabled human therapeutic applications of hepatocyte-targeting GalNAc-conjugated oligonucleotides. This delivery platform has revolutionized the RNA-based therapeutics field. Three GalNAc-conjugated RNAi therapeutics have been approved so far: GIVLAARI® (givosiran, 2019) for treating acute hepatic porphyria, the only drug available to treat this disease, OXLUMO® (lumasiran, 2020, 2021) for the treatment of primary hyperoxaluria type 1 in both adult and pediatric populations, and Leqvio (inclisiran, 2020) for treatment of a highly prevalent global disease hypercholesterolemia. Several other GalNAc-conjugated siRNAs are being evaluated. 

The next frontier is treatment of diseases of extra-hepatic tissues such as the central nervous system and the eye, and potential delivery platforms are currently being evaluated at Alnylam.

Speakers

15:05-15:20
Building partnerships: an introduction to the MRC/UKRI Nucleic Acid Therapy Accelerator

Abstract

The Nucleic Acid Therapy Accelerator (NATA) is a newly founded MRC funded research initiative based on the Harwell Research Campus with a mission to accelerate the development of nucleic acid therapeutics, building partnerships with industry and academia from around the world.

NATA is uniquely placed to establish novel expertise and build partnerships to advance the development of nucleic acid therapeutics for the treatment of both rare and common diseases. Our mission is to provide access to expertise and infrastructure that will establish NATA and the UK as an international centre of excellence for nucleic acid-based therapies.

Speakers

15:20-15:35
Regulatory paths for oligotherapeutics

Speakers

15:35-15:50
Q&A panel

Chair


Speakers

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