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Defining a Midgestational Window for In Utero Genome Editing of the Fetal Murine Cortex
Cameron R Jackson1, Máté Borsos1, Nathan Appling1
1Division of Biology and Biological Engineering, Caltech, Pasadena, CA 91125.
Biorxiv : the Preprint Server for Biology
|May 7, 2026
Summary
Researchers developed a prenatal gene editing platform in mice, enabling precise genetic modifications in the developing brain. This breakthrough offers new avenues for studying and potentially treating congenital brain disorders before birth.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Congenital disorders of cortical development result from genetic issues affecting neurogenesis and neuronal migration.
- Current prenatal tools for modeling or correcting these brain defects are limited.
Purpose of the Study:
- To establish a platform for systemic in utero gene delivery and genome editing in the mouse central nervous system (CNS) at midgestation.
- To enable functional modeling of congenital CNS disorders and explore prenatal therapeutic interventions.
Main Methods:
- Developed a surgical window for fetal circulation access via the vitelline vein at embryonic day 12.5 (E12.5).
- Utilized adeno-associated virus (AAV)-mediated gene delivery and CRISPR/Cas9 genome editing.
- Employed barcoded capsid screens to assess AAV tropism at different developmental stages.
- Demonstrated gene knockout, precise genome modification, and allele installation using homology-directed repair.
Main Results:
- Achieved robust CNS transduction with reduced peripheral off-target expression at E12.5.
- AAV9 showed developmental stage-dependent tropism, favoring CNS at E12.5.
- Successfully recapitulated reeler-like cortical malformations via Reln knockout.
- Demonstrated precise editing, including epitope tagging and pathogenic allele insertion, in neural progenitors and differentiated neurons.
Conclusions:
- Established a permissive midgestational window for prenatal genome editing in the mouse cortex.
- The platform facilitates functional modeling of congenital CNS disorders.
- Provides a foundation for exploring early therapeutic interventions with minimized systemic exposure.
