Gene targeting therapies – what does the future hold for neurological disorders?

An overview of antisense oligonucleotide therapies in development for neurodegenerative diseases.

  • Mon 27th Jan 2020

There are no effective disease modifying therapies for neurodegenerative diseases such as Alzheimer’s (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS) or Huntington’s disease (HD). Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease and the genetic predictability of HD provides an opportunity for early therapeutic intervention many years before overt symptom onset and at a time when reversal or prevention of neural dysfunction may still be possible. As HD is monogenetic, fully penetrant, and characterised by a long premanifest phase, it is emerging as a potential model for studying therapeutic intervention in other neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease where no preclinical diagnostic tests exist. In addition, HD manifests with a broad range of clinical symptoms and signs, many of them common to these other diseases, and involves widespread pathology throughout most of the brain involving similar protein misfolding. Understanding of HD pathogenesis is evolving, and I will present an overview of important approaches in development for targeting mutant HTT DNA and RNA, the cause of HD pathogenesis, and in particular I will present our recent successful phase 1b/2a clinical trial testing the effects of antisense oligonucleotide therapy (ASO) with RG6042 (formerly known as IONIS HTT Rx) in patients with early Huntington’s Disease and present the results of the first successful HTT-lowering drug trial (Tabrizi et al New England Journal of Medicine 2019). This study is the first to demonstrate antisense-mediated protein suppression in patients with a neurodegenerative disease. While this particular ASO holds great promise for HD, our findings have broader implications. These data suggest that antisense technology has the potential to provide disease-modifying benefits in other neurodegenerative diseases associated with aberrant production of proteins, including ALS, Alzheimer’s disease and many other diseases that currently lack adequate treatments. In my talk I will review ASO approaches in development for CNS diseases.

Professor Sarah Tabrizi, University College London

Sarah Tabrizi graduated in biochemistry, then medicine from the University of Edinburgh in 1992. She has worked on research into neurodegenerative diseases since her PhD as an MRC clinical training fellow at UCL. After clinical training, she obtained a DH National Clinician Scientist Fellowship in 2002 to work on protein misfolding at UCL. She was promoted to Senior Lecturer and Honorary Consultant Neurologist in 2003, and to Full Professor in 2009. In 2016, she founded the UCL Huntington’s Disease Centre where she is currently the Director. In addition to basic bench science which focuses on basic cellular mechanisms of neurodegeneration focusing on Huntington’s disease (HD), she also leads a large translational research programme in HD that is working towards finding effective disease-modifying treatments. She was the PI of TRACK-HD and Track-On HD, both major international research initiatives aimed at understanding the neurobiology of the neurodegenerative changes in premanifest and early stage HD gene carriers. She was global clinical PI on the world’s first gene silencing study for HD using anti-sense oligonucleotide therapy, sponsored by Ionis pharmaceuticals, the safety study for which successfully completed in December 2017. She serves on several panels including the UK HD association, the European HD Network and NINDS/NIH. She co-founded, with Sir Michael Rawlins, the UK All Party Parliamentary Group for HD in 2010. In 2014, she was elected a Fellow of the UK Academy of Medical Sciences. In 2017 she received the seventh Leslie Gehry Brenner Prize for Innovation in Science awarded by the Hereditary Disease Foundation, and was appointed as a Principal Investigator at the UK Dementia Research Institute Hub. In 2018 she received the Cotzias Award from the Spanish Society of Neurology.

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