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A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases

Individualized genetic therapies - medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one - offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individu...

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Main Authors: Kim-McManus, Olivia (Author) , Gleeson, Joseph G. (Author) , Mignon, Laurence (Author) , Smith Fine, Amena (Author) , Yan, Winston (Author) , Nolen, Nicole (Author) , Demarest, Scott (Author) , Berry-Kravis, Elizabeth (Author) , Finkel, Richard (Author) , Leonard, Stefanie (Author) , Finlayson, Samuel (Author) , Augustine, Erika (Author) , Lyon, Gholson J. (Author) , Schüle-Freyer, Rebecca (Author) , Yu, Timothy (Author)
Format: Article (Journal)
Language:English
Published: 12 November 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-5
ISSN:2041-1723
DOI:10.1038/s41467-024-54077-5
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-024-54077-5
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-024-54077-5
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Author Notes:Olivia Kim-McManus, Joseph G. Gleeson, Laurence Mignon, Amena Smith Fine, Winston Yan, Nicole Nolen, Scott Demarest, Elizabeth Berry-Kravis, Richard Finkel, Stefanie Leonard, Samuel Finlayson, Erika Augustine, Gholson J. Lyon, Rebecca Schule & Timothy Yu
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Summary:Individualized genetic therapies - medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one - offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.
Item Description:Gesehen am 05.08.2025
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-024-54077-5

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