Implications of the FDA’s new plausible mechanism framework for the development of a personalized in vivo prime editing platform
In February 2026, the US Food and Drug Administration (FDA) published a draft guidance on a new plausible mechanism framework for the development and approval of individualized therapies for genetic conditions.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.
Authors
- Madelynn N. Whittaker (ORCID: https://orcid.org/0000-0002-3382-1134)
- Beverly L. Davidson (ORCID: https://orcid.org/0000-0002-3715-6290)
- Ousamah Younoss Soliman (ORCID: https://orcid.org/0000-0002-0175-4221)
- P. McVeigh
- Emily R. Feierman (ORCID: https://orcid.org/0000-0002-2133-5825)
- Alvin Hsu (ORCID: https://orcid.org/0000-0003-4034-2788)
- Mohamad‐Gabriel Alameh (ORCID: https://orcid.org/0000-0002-5672-6930)
- Aidan Quigley
- Angela X. Nan
- Hooda Said (ORCID: https://orcid.org/0000-0002-2989-0209)
- Ryan C Giovenco
- Xiao Wang
- Kiran Musunuru
- David R. Liu
- Rebecca C. Ahrens-Nicklas
Institutions
- Broad Institute (US)
- Children's Hospital of Philadelphia (US)
- Mirna Therapeutics (United States) (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- The American Journal of Human Genetics
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1016/j.ajhg.2026.03.018
- Primary Topic
- Biosimilars and Bioanalytical Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- U.S. Food and Drug Administration
- Common Fund