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

on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC); Anneliene H. Jonker; Elena Alexandra Tataru; Holm Graessner; David Dimmock; Adam Jaffe; Gareth Baynam; James Davies; Shruti Mitkus; Oxana Iliach; Rich Horgan; Erika F. Augustine; Alison Bateman-House; Anna Maria Gerdina Pasmooij; Tim Yu; Matthis Synofzik; Julie Douville; Larissa Lapteva; Philip John Brooks; Daniel O’Connor; Annemieke Aartsma-Rus

doi:10.1038/s41573-024-01059-3

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

on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC)
, Anneliene H. Jonker
, Elena Alexandra Tataru
, Holm Graessner
, David Dimmock
, Adam Jaffe
, Gareth Baynam
, James Davies
, Shruti Mitkus
, Oxana Iliach
, Rich Horgan
, Erika F. Augustine
, Alison Bateman-House
, Anna Maria Gerdina Pasmooij
, Tim Yu
, Matthis Synofzik
, Julie Douville
, Larissa Lapteva
, Philip John Brooks
, Daniel O’Connor

Annemieke Aartsma-Rus^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

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.

Original language	English
Article number	e10486
Pages (from-to)	40-56
Number of pages	17
Journal	Nature Reviews Drug Discovery
Volume	24
Issue number	1
Early online date	4 Nov 2024
DOIs	https://doi.org/10.1038/s41573-024-01059-3
Publication status	Published - 2025

Bibliographical note

Publisher Copyright:
© Springer Nature Limited 2024.

Funding

This article was written on behalf of the International Rare Diseases Research Consortium (IRDiRC) N-of-1 Task Force and Therapies Scientific Committee. Task Force members beyond the authors of this article are V. Hivert, R.-D. Hilgers and J. Morris. The work was supported by the European contract 'European Joint Programme on Rare Diseases' (N degrees 825575). The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of, or reflecting the position of, their organizations.

Funders	Funder number
Task Force and Therapies Scientific Committee	N-of-1
???publication-publication-funding-organisation-not-added???	Ndegrees825575

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10.1038/s41573-024-01059-3

s41573-024-01059-3Final published version, 1.79 MBLicence: Taverne

Cite this

on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC), Jonker, A. H., Tataru, E. A., Graessner, H., Dimmock, D., Jaffe, A., Baynam, G., Davies, J., Mitkus, S., Iliach, O., Horgan, R., Augustine, E. F., Bateman-House, A., Pasmooij, A. M. G., Yu, T., Synofzik, M., Douville, J., Lapteva, L., Brooks, P. J., ... Aartsma-Rus, A. (2025). The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap. Nature Reviews Drug Discovery, 24(1), 40-56. Article e10486. https://doi.org/10.1038/s41573-024-01059-3

@article{c566558bdbe04a19875d00c308abba2a,

title = "The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap",

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.",

author = "\{on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC)\} and Jonker, \{Anneliene H.\} and Tataru, \{Elena Alexandra\} and Holm Graessner and David Dimmock and Adam Jaffe and Gareth Baynam and James Davies and Shruti Mitkus and Oxana Iliach and Rich Horgan and Augustine, \{Erika F.\} and Alison Bateman-House and Pasmooij, \{Anna Maria Gerdina\} and Tim Yu and Matthis Synofzik and Julie Douville and Larissa Lapteva and Brooks, \{Philip John\} and Daniel O{\textquoteright}Connor and Annemieke Aartsma-Rus",

note = "Publisher Copyright: {\textcopyright} Springer Nature Limited 2024.",

year = "2025",

doi = "10.1038/s41573-024-01059-3",

language = "English",

volume = "24",

pages = "40--56",

journal = "Nature Reviews Drug Discovery",

issn = "1474-1776",

publisher = "Nature Research",

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}

on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC), Jonker, AH, Tataru, EA, Graessner, H, Dimmock, D, Jaffe, A, Baynam, G, Davies, J, Mitkus, S, Iliach, O, Horgan, R, Augustine, EF, Bateman-House, A, Pasmooij, AMG, Yu, T, Synofzik, M, Douville, J, Lapteva, L, Brooks, PJ, O’Connor, D & Aartsma-Rus, A 2025, 'The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap', Nature Reviews Drug Discovery, vol. 24, no. 1, e10486, pp. 40-56. https://doi.org/10.1038/s41573-024-01059-3

The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap. / on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC); Jonker, Anneliene H.; Tataru, Elena Alexandra et al.
In: Nature Reviews Drug Discovery, Vol. 24, No. 1, e10486, 2025, p. 40-56.

Research output: Contribution to journal › Review article › peer-review

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T1 - The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap

AU - on behalf of The N-of-1 Task Force of the International Rare Diseases Research Consortium (IRDiRC)

AU - Jonker, Anneliene H.

AU - Tataru, Elena Alexandra

AU - Graessner, Holm

AU - Dimmock, David

AU - Jaffe, Adam

AU - Baynam, Gareth

AU - Davies, James

AU - Mitkus, Shruti

AU - Iliach, Oxana

AU - Horgan, Rich

AU - Augustine, Erika F.

AU - Bateman-House, Alison

AU - Pasmooij, Anna Maria Gerdina

AU - Yu, Tim

AU - Synofzik, Matthis

AU - Douville, Julie

AU - Lapteva, Larissa

AU - Brooks, Philip John

AU - O’Connor, Daniel

AU - Aartsma-Rus, Annemieke

PY - 2025

Y1 - 2025

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AB - 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.

UR - https://www.scopus.com/pages/publications/85208192368

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DO - 10.1038/s41573-024-01059-3

M3 - Review article

AN - SCOPUS:85208192368

SN - 1474-1776

VL - 24

SP - 40

EP - 56

JO - Nature Reviews Drug Discovery

JF - Nature Reviews Drug Discovery

IS - 1

M1 - e10486

ER -

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

Abstract

Bibliographical note

Funding

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