Work

Exploration of a DDX3X Gene Supplementation Therapy Including Expanded Characterization and Novel Findings of Sleep Disturbances in Ddx3x Haploinsufficient Mice

Year: 2025

Type: article

Abstract: Background DDX3X syndrome is a neurodevelopmental disorder caused by mutations in the DEAD-box helicase 3 X-linked ( DDX3X ) gene. It is one of many rare diseases that lack adequate treatment but has characteristics that potentially make it amenable for gene supplementation therapy. Methods An adeno-associated virus serotype 9 (AAV9)-mediated gene supplementation therapy was designed and tested for efficacy and safety in a mouse model of DDX3X syndrome. 182 female Ddx3x +/- mutant and Ddx3x flox/+ control littermates were dosed at postnatal day 1 with AAV9/DDX3X or vehicle and assessed throughout development for phenotypic benefit. To expand the readouts, sleep patterns—a behavior disrupted in patients—was assessed by wireless telemetry. Results No treatment effects were observed in time to reach early postnatal developmental milestones. At 3 months, a dose dependent amelioration in anxiety-like behavior was observed in treated Ddx3x +/- mice and a dose dependent worsening in anxiety-like behavior was observed in treated Ddx3x flox/+ control mice. These treatment effects were not sustained at 12 months and were absent in mice not subjected to prior developmental milestone testing. Significant sleep disturbances were observed in the Ddx3x +/- mice at 4 months, but AAV9/DDX3X had no effect on sleep. Conclusions While the gene therapy design used in this study is not effective, the data suggests that behavior can be modified by altering Ddx3x expression, warranting further exploration of gene therapy as a potential treatment approach. Additionally, the sleep disturbances present in Ddx3x +/- mutant mice phenocopy the reduced sleep quality in patients, further validating this model for research.

Source: Biological Psychiatry Global Open Science

DOI: 10.1016/j.bpsgos.2025.100599

Authors: Andrea Boitnott, Anjala Jiji, Erik J. Plautz, Yuhui Hu, Xin Chen, Steven J. Gray

Institution: The University of Texas Southwestern Medical Center

Language: English

Topic: Virus-based gene therapy research

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,700