The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap

Anneliene H Jonker¹, Elena-Alexandra Tataru^{2

3}, Holm Graessner⁴, David Dimmock⁵, Adam Jaffe⁶, Gareth Baynam^{7

8

9}, James Davies^{10

11

12}, Shruti Mitkus¹³, Oxana Iliach^{14

15}, Rich Horgan¹⁶, Erika F Augustine¹⁷, Alison Bateman-House¹⁸, Anna Maria Gerdina Pasmooij^{19

20}, Tim Yu²¹, Matthis Synofzik^{22

23}, Julie Douville²⁴, Larissa Lapteva²⁵, Philip John Brooks²⁶, Daniel O'Connor²⁷, Annemieke Aartsma-Rus²⁸; N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC)

Affiliations

¹ HTSR, TechMed Centre, University of Twente, Enschede, The Netherlands.
² French National Institute of Health and Medical Research (INSERM), Paris, France.
³ International Rare Diseases Research Consortium (IRDiRC), Paris, France.
⁴ Centre for Rare Diseases, University Hospital Tübingen, Tübingen, Germany.
⁵ Creyon Bio, San Diego, CA, USA.
⁶ School of Clinical Medicine, University of New South Wales, Faculty of Medicine, Sydney, New South Wales, Australia.
⁷ Rare Care Centre, Perth Children's Hospital, Perth, Western Australia, Australia.
⁸ University of Western Australia, Faculty of Health and Medical Sciences, Division of Paediatrics and Telethon Kids Institute, Perth, Western Australia, Australia.
⁹ University of Notre Dame, Medical Faculty, Sydney, New South Wales, Australia.
¹⁰ MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹¹ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹² NIHR Blood and Transplant Research Unit in Precision Cellular Therapeutics, University of Oxford, Oxford, UK.
¹³ Patient Services, Global Genes, Aliso Viejo, CA, USA.
¹⁴ Regulatory Strategy and Policy, Certara, Toronto, Ontario, Canada.
¹⁵ Canadian Organization for Rare Disorders (CORD), Toronto, Ontario, Canada.
¹⁶ Cure Rare Disease, Woodbridge, CT, USA.
¹⁷ Clinical Trials Unit, Kennedy Krieger Institute, Baltimore, MD, USA.
¹⁸ Division of Medical Ethics, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
¹⁹ Science Department, Dutch Medicines Evaluation Board, Utrecht, the Netherlands.
²⁰ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
²¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
²² Research Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²³ Division of Translational Genomics of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany.
²⁴ ASO Discovery and Development, n-Lorem Foundation, Carlsbad, CA, USA.
²⁵ Division of Clinical Evaluation Pharmacology and Toxicology, Food and Drug Administration, Silver Spring, MD, USA.
²⁶ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
²⁷ Regulatory Policy & Early Access, The Association of the British Pharmaceutical Industry (ABPI), London, UK.
²⁸ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. A.M.Aartsma-Rus@lumc.nl.

PMID: 39496921
DOI: 10.1038/s41573-024-01059-3

Review

The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap

Anneliene H Jonker et al. Nat Rev Drug Discov. 2025 Jan.

. 2025 Jan;24(1):40-56.

doi: 10.1038/s41573-024-01059-3. Epub 2024 Nov 4.

Authors

Affiliations

¹ HTSR, TechMed Centre, University of Twente, Enschede, The Netherlands.
² French National Institute of Health and Medical Research (INSERM), Paris, France.
³ International Rare Diseases Research Consortium (IRDiRC), Paris, France.
⁴ Centre for Rare Diseases, University Hospital Tübingen, Tübingen, Germany.
⁵ Creyon Bio, San Diego, CA, USA.
⁶ School of Clinical Medicine, University of New South Wales, Faculty of Medicine, Sydney, New South Wales, Australia.
⁷ Rare Care Centre, Perth Children's Hospital, Perth, Western Australia, Australia.
⁸ University of Western Australia, Faculty of Health and Medical Sciences, Division of Paediatrics and Telethon Kids Institute, Perth, Western Australia, Australia.
⁹ University of Notre Dame, Medical Faculty, Sydney, New South Wales, Australia.
¹⁰ MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹¹ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹² NIHR Blood and Transplant Research Unit in Precision Cellular Therapeutics, University of Oxford, Oxford, UK.
¹³ Patient Services, Global Genes, Aliso Viejo, CA, USA.
¹⁴ Regulatory Strategy and Policy, Certara, Toronto, Ontario, Canada.
¹⁵ Canadian Organization for Rare Disorders (CORD), Toronto, Ontario, Canada.
¹⁶ Cure Rare Disease, Woodbridge, CT, USA.
¹⁷ Clinical Trials Unit, Kennedy Krieger Institute, Baltimore, MD, USA.
¹⁸ Division of Medical Ethics, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
¹⁹ Science Department, Dutch Medicines Evaluation Board, Utrecht, the Netherlands.
²⁰ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
²¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
²² Research Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²³ Division of Translational Genomics of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany.
²⁴ ASO Discovery and Development, n-Lorem Foundation, Carlsbad, CA, USA.
²⁵ Division of Clinical Evaluation Pharmacology and Toxicology, Food and Drug Administration, Silver Spring, MD, USA.
²⁶ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
²⁷ Regulatory Policy & Early Access, The Association of the British Pharmaceutical Industry (ABPI), London, UK.
²⁸ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. A.M.Aartsma-Rus@lumc.nl.

PMID: 39496921
DOI: 10.1038/s41573-024-01059-3

Abstract

In recent years, a small number of people with rare diseases caused by unique genetic variants have been treated with therapies developed specifically for them. This pioneering field of genetic N-of-1 therapies is evolving rapidly, giving hope for the individualized treatment of people living with very rare diseases. In this Review, we outline the concept of N-of-1 individualized therapies, focusing on genetic therapies, and illustrate advances and challenges in the field using cases for which therapies have been successfully developed. We discuss why the traditional drug development and reimbursement pathway is not fit for purpose in this field, and outline the pragmatic, regulatory and ethical challenges this poses for future access to N-of-1 therapies. Finally, we provide a roadmap for N-of-1 individualized therapy development.

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Conflict of interest statement

Competing interests: A.A.-R. is an unpaid board member of the Dutch Centre for RNA Therapeutics and an unpaid board member of the N = 1 Collaborative (N1C). A.B.-H. is an uncompensated volunteer for the n-Lorem Foundation’s Access to Treatment committee. A.J. has received speaking fees from Vertex Biopharmaceuticals. D.D. is an employee of Creyon Bio. H.G. is a Member of the Board of Directors of the N1C. D.O.’C. is involved in the Rare Therapies Launch Pad (RTLP) as representative for the ABPI, a non-financial interaction. J.Da. is co-founder of Nucleome Therapeutics and provides consultancy to the company; and has intellectual property licensed to BEAM therapeutics, receives revenue from this licence and holds personal shares. M.S. has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Biogen, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly and Solaxa, all unrelated to the present manuscript; and is an unpaid board member of the N1C. R.H. is CEO and founder of Cure Rare Disease; CEO and founder of Myofinity Biosciences; and Consultant for Neuromuscular Disease Foundation. T.Y. has received research support for an N = 1 trial in ataxia telangiectasia from EveryONE Medicines, and is named as an inventor on three patents pertaining to antisense oligonucleotide (ASO) treatments for transposon-associated diseases (WO2019055460A1), ataxia telangiectasia (US20230174979A1) and progranulin (US11359199B2); has received scientific consulting fees as pertains to ASO therapies from GeneTx, RegUp and Servier Pharmaceuticals; serves as an unpaid Board Member for the N1C, the Oligonucleotide Therapeutics Society and the Society for RNA Therapeutics; and serves as an unpaid scientific adviser to several rare disease foundations. A.H.-J., E.-A.T, G.B., S.M., O.I., E.F.A., A.M.G.P., J.D., L.L. and P.J.B. declare no competing interests.

References

1. Rare Diseases International. Operational description of rare diseases. Rare Diseases International https://www.rarediseasesinternational.org/fr/definition-operationnelle-d... (2023).
1. Haendel, M. et al. How many rare diseases are there? Nat. Rev. Drug. Discov. 19, 77–78 (2020). - PubMed - PMC
1. Boycott, K. M. & Ardigó, D. Addressing challenges in the diagnosis and treatment of rare genetic diseases. Nat. Rev. Drug. Discov. 17, 151–152 (2018). - PubMed
1. Smith, C. I. E., Bergman, P. & Hagey, D. W. Estimating the number of diseases—the concept of rare, ultra-rare, and hyper-rare. iScience 25, 104698 (2022). - PubMed - PMC
1. Dawkins, H. J. S. et al. Progress in rare diseases research 2010–2016: an IRDiRC Perspective. Clin. Transl. Sci. 11, 11–20 (2018). - PubMed

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The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap

Affiliations

The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

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LinkOut - more resources

Full Text Sources

Medical