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Cellular and Molecular Bioengineering

Cellular and Molecular Bioengineering - Poster Session D

Poster V11 - Widespread gene editing in the brain via in utero delivery of mRNA using acid-degradable lipid nanoparticles

Friday, October 25, 2024
3:30 PM – 4:30 PM EST
Location: Exhibit Hall E, F & G

Introduction: In utero gene editing with mRNA-based therapeutics has the potential to revolutionize the treatment of neurodevelopmental disorders. However, a critical bottleneck in clinical application has been the lack of safe and efficient mRNA delivery vehicles. This study introduces a novel acid-degradable densely PEGylated lipid nanoparticle (ADP-LNP) as a safe and potent delivery vehicle of mRNA.

Materials and

Methods: The safety profile of ADP-LNPs was evaluated by monitoring brain development, body weights of treated mice, and potential adverse effects on fetal development and postnatal growth. The mRNA encapsulated in ADP-LNPs was administered into the brains of Ai9 mouse fetuses via intracerebroventricular (ICV) injection at 15.5 days of gestation. Gene editing efficiency and targeting were assessed 96 hours post-injection and 10 weeks after the injected fetuses were born.

Results, Conclusions, and Discussions: ADP-LNPs exhibit a remarkable safety profile, evidenced by the normal brain development and body weights of treated mice and no detectable adverse effects on fetal development and postnatal growth. The ADP-LNPs could transfect 30% of the fetal brain cells via intracerebroventricular (ICV) injection in the Ai9 mouse model. The transfection efficacy extends to neural stem and progenitor cells, with over 40% of cortical neurons and 60% of hippocampal neurons showing sustained gene editing 10 weeks postnatally. Furthermore, targeting Angelman Syndrome—a paradigmatic neurodevelopmental disorder—we demonstrate that ADP-LNPs carrying Cas9 mRNA and gRNA induce indels in 17% of brain cells within three days postpartum, underscoring the precision and potential of this approach. The findings illuminate the promise of ADP-LNPs as a transformative tool for in utero treatment of neurodevelopmental disorders, leading to high transfection rates with an outstanding safety profile, thereby setting the stage for a new frontier in non-viral gene editing for treating genetic disorders before birth.

Acknowledgements (Optional):