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ResearchIn-Press PreviewGeneticsTherapeutics Open Access | 10.1172/jci.insight.181760

Efficacious genome editing in infant mice with glycogen storage disease type Ia

Benjamin Arnson,1 Ekaterina Ilich,1 Troy von Beck,1 Songtao Li,1 Elizabeth D. Brooks,1 Dorothy Gheorghiu,1 Gordon He,1 Matthew Weinrub,1 Sze Ying Chan,1 Hye-Ri Kang,2 David Courtney,3 Jeffrey Everitt,4 Bryan R. Cullen,5 and Dwight D. Koeberl1

1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

Find articles by Chan, S. in: PubMed | Google Scholar

1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

Find articles by Kang, H. in: PubMed | Google Scholar

1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

Find articles by Courtney, D. in: PubMed | Google Scholar

1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

Find articles by Everitt, J. in: PubMed | Google Scholar

1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

Find articles by Cullen, B. in: PubMed | Google Scholar

1Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, United States of America

2Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States of America

3Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom

4Department of Pathology, Duke University School of Medicine, Durham, United States of America

5Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, United States of America

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Published July 31, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.181760.
Copyright © 2025, Arnson 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 July 31, 2025 - Version history
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Abstract

Glycogen storage disease type Ia (GSD Ia) is caused by a deficiency of glucose-6-phosphatase (G6Pase) in the liver leading to lethal hypoglycemia. Gene therapy with adeno-associated virus (AAV) vectors encoding G6Pase fails to stably treat GSD Ia early in life. We evaluated genome editing in 12 day-old infant mice with GSD Ia using two AAV vectors, one containing Cas9 from Streptococcus pyogenes and a second Donor vector that expresses a guide RNA and a G6PC transgene. Gene therapy with the Donor vector only was compared with genome editing using both Donor and CRISPR vectors. Treatment with genome editing (total vector dose 0.2 to 2E+13 vector genomes/kg) and bezafibrate (to stimulate autophagy) was efficacious as assessed by hypoglycemia prevention and the frequency of transgene integration, which correlated with improved survival. This therapy achieved 5.9% chromosomal transgene integration through homology directed repair, which surpassed a threshold to prevent long-term hepatic complications. No integration was detected in absence of the CRISPR vector. Importantly for safety, CRISPR vector genomes were depleted, and no intact, integrated CRISPR genomes were detected by long-read sequencing. Thus, genome editing warrants further development as a potentially stable treatment for human infants with GSD Ia.  

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