Systemic in utero gene editing as a treatment for cystic fibrosis

• 成果类型: Article
• 署名作者: Ricciardi, Adele S.; Barone, Christina; Putman, Rachael; Quijano, Elias; Gupta, Anisha; Nguyen, Richard; Mandl, Hanna; Piotrowski-Daspit, Alexandra S.; Lopez-Giraldez, Francesc; Luks, Valerie; Freedman-Weiss, Mollie R.; Farrelly, James; Ahle, Samantha; Lynn, Anna Y.; Glazer, Peter M.; Saltzman, W. Mark; Stitelman, David H.; Egan, Marie E.
• 署名单位: Yale University; Yale University; Yale University; Yale University; Yale University; Yale University; Yale University; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12685
• DOI: 10.1073/pnas.2418731122
• 发表日期: 2025-06-10
• 关键词: peptide nucleic-acids; protein corona; nanoparticles; dna; cells; recombination; RECOGNITION; Mutation; density; pnas

摘要

In utero gene editing has the potential to modify disease- causing genes in multiple developing tissues before birth, possibly allowing for normal organ development, disease improvement, and conceivably, cure. In cystic fibrosis (CF), a disease that arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, there are signs of multiorgan disease affecting the function of the respiratory, gastrointestinal, and reproductive systems already present at birth. Thus, treating CF patients early is crucial for preventing or delaying irreversible organ damage. Here, we demonstrate proof- of- concept of multiorgan mutation correction in CF using peptide nucleic acids encapsulated in polymeric nanoparticles and delivered systemically in utero. In utero editing was associated with sustained postnatal CFTR activity, at a level similar to that of wild- type mice, in both respiratory and gastrointestinal tissues, without detection of off- target mutations in partially homologous loci. This work suggests that systemic in utero gene editing represents a viable strategy for treating monogenic diseases before birth that impact multiple tissue types.