Seminar: Emerging Oligonucleotide Therapeutics for Neuromuscular Diseases

MDUK OXFORD NEUROMUSCULAR CENTRE SEMINAR SERIES

ATTENDANCE

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

Hybrid seminar at the IMS-Tetsuya Nakamura Building (IDRM). For the online link, please email chelsea.larabee@idrm.ox.ac.uk.

Students, postdoctoral researchers, and other trainees will be invited to have lunch with Dr. Nishino following the talk. To attend the lunch, please sign up here.

ABSTRACT

The rapid pace of precision medicine development is illustrated by the progress of new therapies for the incurable Duchenne muscular dystrophy (DMD), which has wide-ranging implications for genetic neuromuscular diseases. The current state-of-the-art is an antisense oligonucleotide-based gene therapy designed to skip specific exons to restore the expression of shorter but functional dystrophin. We previously completed an investigator-initiated phase I study with systemic administration of the morpholino antisense NS-065/NCNP-01 (viltolarsen) for exon-53 skipping in patients with DMD, which was recently conditionally approved under accelerated approval mechanisms in Japan and the US. However, a weakness of the current oligonucleotide-based exon-skipping approach is that it is mutation-specific. NS-089/NCNP-02 was developed as the world's first exon 44-skipping drug to expand the number of patients who can benefit from this approach. This skip is expected to benefit 6·2% of all patients with DMD. Here we report the findings of a first-in-human phase I/II study that evaluated the safety, efficacy, and pharmacokinetics of NS-089/NCNP-02 in patients with DMD amenable to exon 44 skipping. Additionally, this was the first study to use mesenchymal urine-derived cells from study patients to evaluate the efficacy of a drug in a DMD clinical trial. Findings from these assays suggest that exon 44 skipping and recovery of dystrophin protein levels can be achieved when an adequate concentration of NS-089/NCNP-02 reaches the skeletal muscle, consistent with the in vivo efficacy. This is of clinical significance, as future clinical trials can utilize this methodology to evaluate the pharmacological efficacy and sequence optimization of morpholino antisense drugs and determine patients' eligibility for specific morpholino antisense treatments. We also discuss the potential of urine-derived cell-based approaches to model human neuromuscular and neurodegenerative diseases.

SPEAKER

Yoshitsugu Aoki, MD, PhD is a renowned medical scientist known for his pioneering work in the development of oligonucleotide treatment for neuromuscular diseases. He completed his Medical degree at Tohoku University, Japan in 2001, and subsequently worked in clinical Neurology, becoming a consultant neurologist in 2008. In 2011, he earned his doctorate in System Neuroscience from the Tokyo Medical and Dental University Graduate School (TMDU), Japan. Dr. Aoki's exceptional research skills and achievements led him to join Prof. Matthew JA Wood's laboratory at the University of Oxford in 2012, where he conducted groundbreaking research in the field of neuromuscular diseases. His exceptional work in this area was recognized by the Royal Society of the UK in 2013, and he was appointed as a Senior Research Scientist, Faculty of Physiological Sciences, University of Oxford in 2014. Currently, Dr. Aoki is the Director of the Department of Molecular Therapy and the head of dystrophic dog and micropig facility at the National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP). He also holds the rank of Adjunct Professor at several prestigious universities, including TMDU, Tokyo University of Agriculture and Technology, Shinshu University School of Medicine, and Waseda University. He is currently leading a clinical trial in Japan called "Systemic administration of the morpholino antisense for exon-44 skipping in Duchenne muscular dystrophy: An investigator-initiated clinical trial phase I/II study," funded by Japan Agency for Medical Research and Development.