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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI197503

AAV-mediated gene therapy in a SLC13A5 citrate transporter disorder model rescues epileptic and metabolic phenotypes

Lauren E. Bailey,1 Raegan M. Adams,1 Morgan K. Schackmuth,1 Irvin T. Garza,1 Krishanna Knight,1 Sydni K. Holmes,1 Meghan M. Eller,1 MinJae Lee,2 and Rachel M. Bailey1

1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

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1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Lee, M. in: PubMed | Google Scholar

1Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, United States of America

2Department of Health Data Science and Biostatistics, University of Texas Southwestern Medical Center, Dallas, United States of America

Find articles by Bailey, R. in: PubMed | Google Scholar |

Published February 19, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI197503.
Copyright © 2026, Bailey et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 19, 2026 - Version history
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Abstract

SLC13A5 citrate transporter disorder is a rare epileptic encephalopathy caused by loss of function pathogenic variants in the SLC13A5 gene. Loss of sodium/citrate cotransporter (NaCT) function causes a severe early life epilepsy resulting in life-long developmental disabilities and increased extracellular citrate. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and neurodevelopmental SLC13A5 phenotype. We performed preclinical studies in SLC13A5 deficient mice evaluating phenotype rescue with adeno-associated virus (AAV) vector carrying a functional copy of the human SLC13A5 gene (AAV9/SLC13A5). Cerebrospinal fluid-delivery of AAV9/SLC13A5 decreased extracellular citrate levels, normalized electrophysiologic and sleep architecture abnormalities, and restored resistance to chemically induced seizures and death. Treatment benefits were achieved with administration during early brain development and in young adult mice, indicating therapeutic efficacy across developmental and post-developmental stages. Comparison of delivery routes in young adult KO mice showed that higher brain targeting achieved with intra-cisterna magna delivery resulted in greater treatment benefit as compared to intrathecal lumbar puncture delivery. Together, these results support further development of AAV9/SLC13A5 for treating SLC13A5 citrate transporter disorder.

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