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Tailored RNA therapies for ultrarare CNS diseases & mutations: a criteria framework for patient ID

Tailored n-of-1 RNA treatment approaches targeting ultrarare or even private variants have opened up a qualitatively novel realm of treatments for rare diseases and single patients who have so far been deemed untreatable. While highly promising and innovative, identification of patients that not only qualify but are highly likely to benefit from such approaches is difficult - involving a complex melange of biological, clinical, psychological and ethical aspects. To facilitate orientation and guidance, we here propose a framework that allows the identification of suitable patients for tailored therapeutic ASO approaches based on transparent criteria that enable a comprehensive assessment of the individual benefit-risk balance, taking into account characteristics of (i) the underlying variant, (ii) disease as well as (iii) the individual patient.

Professor Dr. Matthis Synofzik, MD, is head of the research division “Translational Genomics of neurodegenerative diseases” at the Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Germany. His focuses on unravelling the molecular basis of both autosomal-dominant and autosomal-recessive ataxias, motor neuron diseases and dementias (identification of >105novel disease genes), identifying translational molecular and digital-motor biomarkers, and preparing targeted treatments. This includes an innovative n-of-1 antisense oligonucleotide (ASO) program, where he is part of the steering committees of both the European “1 Mutation 1 Medicine” (1M1M) and the transatlantic “N-of-1 Collaborative” (N1C) programs. He has a broad research and clinical background with specific expertise in next-generation genomics, deep-phenotyping, and translational studies, with now >300 PubMed listed peer-reviewed publications on these neurogenetic conditions (h-index 59), including BRAIN, NEURON, NEW ENGLANG JOURNAL OF MEDICINE. Matthis leads several worldwide EU-funded consortia on genetic ataxias like “PREPARE”, „PROSPAX” and “EVIDENCE-RND”, is PI of the EU-funded consortium “TREAT-ARCA” , and serves as co-lead of the global trial-readiness platform “ATAXIA GLOBAL INITIATIVE” (AGI) (total amount of third-party funding: > 7 million €). He coordinates the international multicenter prospective longitudinal database on recessive ataxias (“ARCA registry”), which brings together >25 world-leading ataxia centers.

Rebecca Schüle, MD is the leader of the Genomics of Rare Movement Disorders research group within the Hertie Institute for Clinical Brain Research at the University of Tübingen in Germany. Whilst she conducts research across a spectrum of neurodegenerative diseases, she has a special interest and focuses on HSP on which she is widely published and recognised as a global leader in the field. Rebecca created and developed the Spastic Paraplegia Rating Scale (SPRS) which is the only widely accepted and used measure of HSP status currently. Rebecca combines clinical practice as a neurologist with her research. She has practical outcomes focus on the research that she does for the benefit of the people affected. Rebecca has undertaken several clinical trials in HSP and has followed the progression of HSP in around 600 patients for around 10 years. She is in the process of authoring a natural history of SPG4, the predominant form of HSP and is studying potential biomarkers of disease severity in HSP. She is coordinating the international TreatHSP network, an association of HSP clinicians and researchers with the aim to develop, prepare and implement novel therapies for people affected by HSP.



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