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

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 and Timothy Yu
Additional contact information
Olivia Kim-McManus: Rady Children’s Institute for Genomic Medicine
Joseph G. Gleeson: Rady Children’s Institute for Genomic Medicine
Laurence Mignon: n-Lorem Foundation
Amena Smith Fine: Kennedy Krieger Institute
Winston Yan: N=1 Collaborative
Nicole Nolen: N=1 Collaborative
Scott Demarest: Children’s Hospital Colorado
Elizabeth Berry-Kravis: Rush University Medical Center
Richard Finkel: St. Jude Children’s Research Hospital
Stefanie Leonard: N=1 Collaborative
Samuel Finlayson: Seattle Children’s Hospital
Erika Augustine: Kennedy Krieger Institute
Gholson J. Lyon: New York State Institute for Basic Research in Developmental Disabilities
Rebecca Schule: Heidelberg University Hospital
Timothy Yu: N=1 Collaborative

Nature Communications, 2024, vol. 15, issue 1, 1-5

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54077-5

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