Online Seminar: Tricyclo-DNA: promising antisense oligonucleotides for the treatment of neuromuscular diseases

This seminar is intended for the personnel and students at the University of Oxford and the Oxford University Hospitals Foundation Trust.

Online Seminar – please register for the Zoom meeting in advance.

Antisense oligonucleotides (ASO) hold promise for therapeutic splice-switching correction in many genetic diseases; however, despite advances in chemistry and design, systemic use of ASOs is still limited due to poor tissue/cellular uptake. This talk will describe the therapeutic potential of ASOs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake in many tissues after systemic administration. These outstanding properties have been demonstrated in different mouse models of genetic diseases such as Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA).  DMD is a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. While current naked ASOs do not significantly enter the heart or cross the blood brain barrier, systemic delivery of tcDNA-ASOs allow high levels of dystrophin rescue in skeletal muscles as well as in heart and to a lower extent in the brain. Our results have demonstrated physiological improvement of the cardio-respiratory functions and correction of behavioural features linked to the emotional/cognitive deficiency associated with the lack of dystrophin. Although initial results indicated an encouraging safety profile for tcDNA-ASOs in mice, we showed a clear impact of phosphorothioate bonds (PS) on their biodistribution, efficacy but also toxicity. Moreover our work on the human DMD exon 51 revealed a sequence-dependent toxicity of some PS-tcDNA-ASO candidates, which we characterized and eliminated using a new detoxification method. Altogether, these findings led us to develop a new generation of PS-free tcDNA-ASO, conjugated to a lipid, displaying a much higher therapeutic index and safer toxicological profile. A clinical trial evaluating this new generation of conjugated tcDNA-ASO is currently being prepared. 

Dr Aurélie Goyenvalle is directing a research group at the University of Versailles focused on gene and antisense therapies for the treatment of neuromuscular disorders. Aurelie received her PhD in Virology at the University of Paris VII in 2006 from her work at Genethon in France, where she developed an exon-skipping gene therapy strategy for Duchenne muscular dystrophy (DMD) using adeno-associated virus vectors (AAV) encoding chimeric U7snRNA constructs carrying antisense sequences. To pursue her interest in gene therapy and splicing modulation approaches for DMD, she joined Prof. Kay Davies’ laboratory at the University of Oxford as a post-doctoral scientist supported by an EMBO fellowship. During her postdoc Aurélie developed various splicing modulation approaches including the optimization of the U7 snRNA system for neuromuscular and neurodegenerative diseases, and the evaluation of peptide-conjugated antisense oligonucleotides. In 2011, she joined the Institute of Myology in Paris to investigate splice switching approaches using novel antisense oligonucleotides and in 2012, she was awarded a Chair of Excellence program to establish her own group at the University of Versailles to develop novel RNA based technology for the treatment of neuromuscular diseases. In this context, she has notably demonstrated the therapeutic potential of a novel class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake in many tissues after systemic administration. In 2015, Aurélie has been appointed a permanent research scientist position by the French national institute for health and medical research (INSERM) to pursue this line of research and she is currently head of a team evaluating splice-switching approach for various genetic disorders.