A scalable and equitable framework for target and patient prioritisation in rare disease antisense therapeutics
Abstract
Abstract Background Nucleic acid therapies (NATs) comprise engineered DNA- or RNA-based medicines that act through sequence-specific interactions to modify gene function. Among these, antisense oligonucleotide (ASO) therapies are designed to bind messenger RNA (mRNA) or pre-mRNA to alter splicing, transcript stability, or translation. Many patients with a rare genetic disease stand to benefit from these treatments and, as underlying technologies continue to advance, a critical barrier to care is the equitable selection of targets and patients. Owing to landmark progress in genomic health care, the UK is uniquely positioned to develop a national framework on NAT patient-selection infrastructure. The UK Platform for Nucleic Acid Therapies (UPNAT) has been launched, in part, to meet this goal, with a key output being a structured patient and target selection framework to support NAT development and clinical application, using ASO therapies as a pilot modality. Methodology and Results A multidisciplinary panel of UK-based experts established the UPNAT framework to enable systematic assessment of ASO amenability across modular domains encompassing disease understanding, functional models, variant characteristics, and the individual patient, incorporating the recently published N1C VARIANT guidelines. This modular structure supports consistent prioritisation of tractable targets while identifying biological, clinical, technical, or evidentiary gaps currently limiting ASO development. Designed for implementation within the UK healthcare infrastructure and amenable to future automation using open-access resources, the framework was iteratively refined through application to genomic and clinical data from approved ASO therapies and selected real-world patient case studies. Conclusion We present the first disease-agnostic framework to support structured prioritisation of patients and targets (diseases, genes, or variants) for ASO development and consideration within specialist healthcare services. Designed to accommodate rapid technological advances in NATs, the framework promotes transparent, equitable, and reproducible decision-making within the UK National Health Service (NHS), with principles transferable to other healthcare systems.
Authors 32
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Affiliation as printed
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
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Centre for Human Genetics · University of Oxford
Affiliation as printed
Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
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Cambridge University Hospitals NHS Foundation Trust · Genomics England
Affiliation as printed
Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Genomics England, One Canada Square, London, UK
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Affiliation as printed
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Genetic Therapy Accelerator Centre, UCL Queen Square Institute of Neurology, London, UK
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Moorfields Eye Hospital NHS Foundation Trust · Max Planck Society · University College London
Affiliation as printed
Centro Universitário Max-Planck (UniMAX), São Paulo, Brazil
Moorfields Eye Hospital NHS Foundation Trust, London, UK
UCL Institute of Ophthalmology 11-43 Bath Street, London, UK
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University of Oxford · Oxford University Hospitals NHS Trust
Affiliation as printed
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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University of Oxford · Oxford University Hospitals NHS Trust
Affiliation as printed
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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University of Oxford · Oxford University Hospitals NHS Trust
Affiliation as printed
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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Affiliation as printed
Clinical Genetics Service, Great Ormond Street Hospital, London, UK
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Affiliation as printed
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
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UCL Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuroinflammation, UCL Institute of Neurology, London, UK
NIHR University College London Hospitals Biomedical Research Centre, London, UK
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Affiliation as printed
Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK
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Moorfields Eye Hospital NHS Foundation Trust · University College London
Affiliation as printed
Moorfields Eye Hospital NHS Foundation Trust, London, UK
UCL Institute of Ophthalmology 11-43 Bath Street, London, UK
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Affiliation as printed
Boston Children’s Hospital, Boston, MA, USA
N=1 Collaborative, 7 Carole Place, Somerville, MA, USA
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UCL Biomedical Research Centre · NIHR Great Ormond Street Hospital Biomedical Research Centre · University College London
Affiliation as printed
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, UK
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Leiden University Medical Center · University of Oxford
Affiliation as printed
Dutch Center for RNA Therapeutics, Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Institute of Developmental and Regenerative Medicine (IDRM), Department of Paediatrics, University of Oxford, Oxford, UK
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Affiliation as printed
MRC Nucleic Acid Therapy Accelerator, Research Complex at Harwell, UK
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Association of the British Pharmaceutical Industry
Affiliation as printed
The Association of the British Pharmaceutical Industry (ABPI), London, UK
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Cambridge University Hospitals NHS Foundation Trust · Genomics England
Affiliation as printed
Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Genomics England, One Canada Square, London, UK
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Affiliation as printed
Institute of Developmental and Regenerative Medicine (IDRM), Department of Paediatrics, University of Oxford, Oxford, UK
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Affiliation as printed
Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK
Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, Great Ormond Street Institute of Child Health
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Birmingham Women's Hospital · Birmingham Women’s and Children’s NHS Foundation Trust · University of Birmingham
Affiliation as printed
Clinical Genetics, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK
Clinical Sciences Department, University of Birmingham, Birmingham, UK
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Affiliation as printed
Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK
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Affiliation as printed
UCL Institute of Ophthalmology 11-43 Bath Street, London, UK
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Centre for Human Genetics · University of Oxford
Affiliation as printed
Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
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Affiliation as printed
Institute of Developmental and Regenerative Medicine (IDRM), Department of Paediatrics, University of Oxford, Oxford, UK
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UCL Biomedical Research Centre · NIHR Great Ormond Street Hospital Biomedical Research Centre · University College London
Affiliation as printed
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, UK
The Dubowitz Neuromuscular Centre, Developmental Neurosciences Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
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UCL Biomedical Research Centre · NIHR Great Ormond Street Hospital Biomedical Research Centre · University College London
Affiliation as printed
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, UK
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Moorfields Eye Hospital NHS Foundation Trust · University College London
Affiliation as printed
Moorfields Eye Hospital NHS Foundation Trust, London, UK
UCL Institute of Ophthalmology 11-43 Bath Street, London, UK
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University of Cambridge · UK Dementia Research Institute · NIHR Cambridge Biomedical Research Centre · University College London
Affiliation as printed
Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
UK Dementia Research Institute at The University of Cambridge, Cambridge, UK
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