LNP Delivery of Prime Editors Enables Durable Correction of PAH R408W in Phenylketonuria Models
- 1Moderna
Abstract
Phenylketonuria (PKU) is a monogenic metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, the most common of which is c.1222C>T (p.R408W). Current treatment options, including dietary restriction and enzyme substitution, can be effective but are often challenging for patients to maintain and do not address the underlying genetic defect. Gene editing represents a compelling one-time treatment approach for PKU. Herein, we demonstrate mRNA:LNP-mediated delivery of prime editors that enable therapeutically-relevant levels of correction of the R408W mutation in both in vitro and in vivo model systems. Further, we found that co-delivery of the DNA repair modulator RAD18 and engineering of the prime editor protein, enabled 2-fold and 3-fold increases in prime editing relative to PE3 respectively, resulting in ~50% correction efficiency in a humanized PKU mouse model. Collectively, this work identifies novel potential approaches to enhancing prime editing and establishes LNP-delivered prime editing as a mutation-specific, non-viral therapeutic strategy for PKU, as well as providing a framework for extending prime editing to other inherited liver diseases.
Related
- Sepiapterin Enables Liberalisation of Natural Protein Intake While Improving Metabolic Control in Adolescents with Phenylketonuria
- Early detection of immunoglobulin A against a vaccine backbone protein enables fast, durable, and objective identification of individuals vaccinated against Ebola virus
- Lipid Nanoparticle Delivery of CAR276 mRNA Enables Antigen-Specific Cytotoxicity in T Cells Against Glioblastoma Cells
- Mapping intronic mutational hotspots by in silico mutagenesis enables single antisense oligonucleotide correction of multiple variants
- “It’s Like a Whole Set of Things That We Do”: A Qualitative Study of the Roles of Journal Editors-in-Chief
BibTeX
@misc{yazinski2026delivery,
title = {{LNP Delivery of Prime Editors Enables Durable Correction of PAH R408W in Phenylketonuria Models}},
author = {S. Yazinski and S. Canali and Y. Xu and X. Zhu and J. Nelson and W. Gao and Z. Daniloski and W. Leung-Owen and F. Winkler and A. Frassetto and A. Simon and J. Penterman and S. Maguire and D. Fuchs and J. Rybarski and T. Towner and V. Bhatia and K. Ramachandran and K. Anderson and S. Shamanth Donthi and Y. Kelkar and E. J. Jung and X. Yan and L. Stretz and M. Wulf and M. Severson and B. Reznik and S. O'Hayre and E. Huang and A. Forget and K. McKinney and P. Finn},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.753751},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.753751v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - LNP Delivery of Prime Editors Enables Durable Correction of PAH R408W in Phenylketonuria Models
AU - S. Yazinski
AU - S. Canali
AU - Y. Xu
AU - X. Zhu
AU - J. Nelson
AU - W. Gao
AU - Z. Daniloski
AU - W. Leung-Owen
AU - F. Winkler
AU - A. Frassetto
AU - A. Simon
AU - J. Penterman
AU - S. Maguire
AU - D. Fuchs
AU - J. Rybarski
AU - T. Towner
AU - V. Bhatia
AU - K. Ramachandran
AU - K. Anderson
AU - S. Shamanth Donthi
AU - Y. Kelkar
AU - E. J. Jung
AU - X. Yan
AU - L. Stretz
AU - M. Wulf
AU - M. Severson
AU - B. Reznik
AU - S. O'Hayre
AU - E. Huang
AU - A. Forget
AU - K. McKinney
AU - P. Finn
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.753751
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.753751v1
AB - Phenylketonuria (PKU) is a monogenic metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, the most common of which is c.1222C>T (p.R408W). Current treatment options, including dietary restriction and enzyme substitution, can be effective but are often challenging for patients to maintain and do not address the underlying genetic defect. Gene editing represents a compelling one-time treatment approach for PKU. Herein, we demonstrate mRNA:LNP-mediated delivery of prime editors that enable therapeutically-relevant levels of correction of the R408W mutation in both in vitro and in vivo model systems. Further, we found that co-delivery of the DNA repair modulator RAD18 and engineering of the prime editor protein, enabled 2-fold and 3-fold increases in prime editing relative to PE3 respectively, resulting in ~50% correction efficiency in a humanized PKU mouse model. Collectively, this work identifies novel potential approaches to enhancing prime editing and establishes LNP-delivered prime editing as a mutation-specific, non-viral therapeutic strategy for PKU, as well as providing a framework for extending prime editing to other inherited liver diseases.
ER -