Implications of the FDA’s new plausible mechanism framework for the development of a personalized in vivo prime editing platform

The American Journal of Human Genetics 2026 Open access

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Authors: Emily Feierman, Madelynn N. Whittaker, Aidan Quigley, Dominique L. Brooks, P. McVeigh, Angela X. Nan, Alvin Hsu, Hooda Said, Ousamah Younoss Soliman, Ryan C Giovenco, Beverly L. Davidson, Mohamad‐Gabriel Alameh
+4 more David R. Liu, Xiao Wang, Kiran Musunuru, Rebecca C. Ahrens-Nicklas
DOI: 10.1016/j.ajhg.2026.03.018
Cited by: 2
References: 23

Abstract

In February 2026, the US Food and Drug Administration (FDA) published a draft guidance on a new plausible mechanism framework for the development and approval of individualized therapies for genetic conditions. Here, we report initial proof-of-concept studies supporting a customizable prime editing platform geared to the treatment of 7 urea cycle disorders (UCDs) and other liver-centered disorders, as well as the outcome of a formal meeting with the FDA to discuss the use of the platform in an "umbrella-of-umbrellas" clinical trial including subjects with any of the 7 UCDs. We anticipate our findings will be of interest to academic investigators and industry sponsors who wish to pursue expeditious FDA approvals of therapies for ultra-rare diseases using the plausible mechanism framework.

Fields of Study & Subjects

Biosimilars and Bioanalytical Methods CRISPR and Genetic Engineering Monoclonal and Polyclonal Antibodies Research

Publication details

Journal / source
The American Journal of Human Genetics
Publisher
Elsevier BV
Volume
113
Issue
5
Pages
891–899
Publication date
31 March 2026
Language
EN