Lipid nanoparticle vector for prenatal gene therapy treatment of apert syndrome

The National Institute of Child Health and Human Development awarded the University of California, San Francisco $172,160 on December 17, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to develop lipid nanoparticle vectors for prenatal gene therapy treatment of Apert syndrome.

The research uses induced pluripotent stem cells from patients with Apert syndrome to test whether RNAi and CRISPR/Cas9 nucleic acid constructs loaded onto lipid nanoparticles can potently and specifically abrogate the molecular effects of the disorder in vitro, and whether lipid nanoparticles can deliver nucleic acids to fetal mouse craniofacial tissues after in utero injection. Apert syndrome is a genetic disorder caused by mutations in fibroblast growth factor receptor-2 that results in severe congenital craniofacial deformities; current treatment relies on postnatal reconstructive surgery, which leaves severe residual deformity. The long-term objective is to develop prenatal gene therapy to enhance lives and optimize function for patients with Apert syndrome. Work is performed in San Francisco, California, with a period of performance ending June 30, 2028.

Abstract

Apert syndrome (as), a genetic disorder caused by mutations in fibroblast growth factor receptor-2 (FGFR2), is characterized by severe congenital deformities of the craniofacial skeleton, resulting in lifelong challenges for affected children. The only treatment for as is postnatal reconstructive surgery which, despite state-of-the-art care, results in severe residual deformity, underscoring the need for better alternative therapies. Because IT is a monogenic disorder that manifests in utero, as is a promising candidate for treatment with prenatal genetic therapy. Various gene editing/suppression strategies in in vitro and small animal models of as have been shown to abrogate the disease phenotypes but thus far, these potential therapies have high potential for off- target effects. Lipid nanoparticles (lnps) have been shown to be a safe and effective vector for delivering highly specific nucleic acid-based gene therapies but have not been evaluated in as or other congenital craniofacial disorders. The goals of this study are to better understand the effects of LNP-delivered precise genetic modulating agents on FGFR2 signaling in as human cells and to adapt these state-of-the-art technologies for targeting craniofacial tissues. The long-term objective of this study is to develop prenatal gene therapy to enhance lives, decrease suffering, and optimize the function of patients with as. The hypotheses of this study are that 1) rnai and crispr/CAS9 nucleic acid constructs loaded onto lnps can potently and specifically abrogate human as molecular effects in vitro, and 2) that lnps can deliver nucleic acids to fetal mouse craniofacial tissues after in utero injection. These hypotheses will be tested in two specific aims. In aim 1, this study will use induced pluripotent stem cells from patients with as differentiated along osteogenic lineages and lnps loaded with nucleic acids encoding for rnai and crispr/CAS9 constructs to evaluate the molecular effects of targeting as-specific human gene mutations. In aim 2, this study will use a mouse model to characterize in utero delivery of various lnps to embryonic craniofacial tissues. These studies will be conducted by the principal investigator at the university of california-SAN francisco as part of a two-year structured research fellowship training plan that will include conceptual didactic learning, lab-based research training, and extensive opportunities for scientific data analysis, writing, and presentation. Mentorship will be provided by a team of sponsors and collaborators with expertise in the topic and a track-record of fostering future surgeon-scientists. Successful completion of the proposed aims is expected to advance our knowledge about highly specific potential treatment modalities for as in humans, and to help characterize the potential for incorporating lnps into prenatal human treatment strategies of as and many other craniofacial disorders.