CoChat
Sign Up
Cited by 30Virus-based gene therapy researchGlycogen Storage Diseases and MyoclonusLysosomal Storage Disorders Research

Safety and Efficacy of DTX401 , an AAV8 ‐Mediated Liver‐Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a ( GSDIa )

Open access
Weinstein, David A., Derks, Terry G., Rodriguez‐Buritica, David F., Ahmad, Ayesha, Couce, María‐Luz, Mitchell, John J., Riba‐Wolman, Rebecca, Mount, Malaya +11 more·2025·Journal of Inherited Metabolic Disease
DOI 10.1002/jimd.70014PMC PMC11893205
Open this paper in CoChat — free accountOpen PDF

Abstract

Glycogen storage disease type Ia (GSDIa) is a rare, life‐threatening, inherited carbohydrate metabolism disorder caused by glucose‐6‐phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno‐associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open‐label, phase 1/2, dose‐escalation, 52‐week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 10 12 genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 10 12 GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment‐emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose‐limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment‐related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); p < 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/jimd.70014

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gene therapy involving viral-mediated transfer of glucose-6-phosphatase is currently being evaluated in maintaining euglycemia and reducing dependence on cornstarch, with promising results in a phase II trial.

    “Gene therapy involving viral-mediated transfer of glucose-6-phosphatase is also currently being evaluated in maintaining euglycemia and reducing dependence on cornstarch, with promising results in a phase II trial [40].”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [40]

    The Results (Efficacy Outcomes) report maintained or increased time in euglycemia despite substantially reduced cornstarch intake, supporting the promising-results claim. The Trial Design section identifies the study as a phase 1/2 trial, not a phase II trial. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 36

  1. [1]D. S. Bali, A. El‐Gharbawy, S. Austin, S. Pendyal, and P. S. Kishnani. 2006. “ Glycogen Storage Disease Type I,” In GeneReviews® [Internet], edited by M. P. Adam, D. B. Everman, G. M. Mirzaa, et al. University of Washington. 20301489
  2. [2]J. Y. Chou, H. S. Jun, and B. C. Mansfield, “ Glycogen Storage Disease Type I and G6Pase‐Beta Deficiency: Etiology and Therapy,” Nature Reviews Endocrinology 6, no. 12 (2010): 676– 688, 10.1038/nrendo.2010.189. PMC4178929 20975743 · DOI
  3. [3]T. G. J. Derks, D. F. Rodriguez‐Buritica, A. Ahmad, et al., “ Glycogen Storage Disease Type Ia: Current Management Options, Burden and Unmet Needs,” Nutrients 13, no. 11 (2021): 3828, 10.3390/nu13113828. 34836082 PMC8621617 · DOI
  4. [4]P. S. Kishnani, S. L. Austin, J. E. Abdenur, et al., “ Diagnosis and Management of Glycogen Storage Disease Type I: A Practice Guideline of the American College of Medical Genetics and Genomics,” Genetics in Medicine 16, no. 11 (2014): e1– e29, 10.1038/gim.2014.128. 25356975 · DOI
  5. [5]J. T. Jacoby, B. Bento Dos Santos, T. Nalin, et al., “ Bone Mineral Density in Patients With Hepatic Glycogen Storage Diseases,” Nutrients 13, no. 9 (2021): 2987, 10.3390/nu13092987. 34578865 PMC8469033 · DOI
  6. [6]G. O. Okechuku, L. R. Shoemaker, M. Dambska, L. M. Brown, J. Mathew, and D. A. Weinstein, “ Tight Metabolic Control Plus ACE Inhibitor Therapy Improves GSD I Nephropathy,” Journal of Inherited Metabolic Disease 40, no. 5 (2017): 703– 708, 10.1007/s10545-017-0054-2. 28612263 · DOI
  7. [7]D. A. Weinstein and J. I. Wolfsdorf, “ Effect of Continuous Glucose Therapy With Uncooked Cornstarch on the Long‐Term Clinical Course of Type 1a Glycogen Storage Disease,” European Journal of Pediatrics 161, no. Suppl 1 (2002): S35– S39, 10.1007/s00431-002-1000-2. 12373568 · DOI
  8. [8]M. Dambska, E. B. Labrador, C. L. Kuo, and D. A. Weinstein, “ Prevention of Complications in Glycogen Storage Disease Type Ia With Optimization of Metabolic Control,” Pediatric Diabetes 18, no. 5 (2017): 327– 331, 10.1111/pedi.12540. 28568353 · DOI
  9. [9]N. T. Lawrence, T. Chengsupanimit, L. M. Brown, T. G. Derks, G. P. Smit, and D. A. Weinstein, “ Inflammatory Bowel Disease in Glycogen Storage Disease Type Ia,” Journal of Pediatric Gastroenterology and Nutrition 64, no. 2 (2017): e52– e54, 10.1097/MPG.0000000000000592. 25304890 · DOI
  10. [10]S. F. Garbade, V. Ederer, P. Burgard, et al., “ Impact of Glycogen Storage Disease Type I on Adult Daily Life: A Survey,” Orphanet Journal of Rare Diseases 16, no. 1 (2021): 371, 10.1186/s13023-021-02006-w. 34479584 PMC8414849 · DOI
  11. [11]T. A. H. Steunenberg, F. Peeks, I. J. Hoogeveen, et al., “ Safety Issues Associated With Dietary Management in Patients With Hepatic Glycogen Storage Disease,” Molecular Genetics and Metabolism 125, no. 1–2 (2018): 79– 85, 10.1016/j.ymgme.2018.07.004. 30037503 · DOI
  12. [12]R. M. Beaty, M. Jackson, D. Peterson, et al., “ Delivery of Glucose‐6‐Phosphatase in a Canine Model for Glycogen Storage Disease, Type Ia, With Adeno‐Associated Virus (AAV) Vectors,” Gene Therapy 9, no. 15 (2002): 1015– 1022, 10.1038/sj.gt.3301728. 12101432 · DOI
  13. [13]D. D. Koeberl, C. Pinto, B. Sun, et al., “ AAV Vector‐Mediated Reversal of Hypoglycemia in Canine and Murine Glycogen Storage Disease Type Ia,” Molecular Therapy 16, no. 4 (2008): 665– 672, 10.1038/mt.2008.15. 18362924 · DOI
  14. [14]D. A. Weinstein, C. E. Correia, T. Conlon, et al., “ Adeno‐Associated Virus‐Mediated Correction of a Canine Model of Glycogen Storage Disease Type Ia,” Human Gene Therapy 21, no. 7 (2010): 903– 910, 10.1089/hum.2009.157. 20163245 PMC2938360 · DOI
  15. [15]A. Zingone, H. Hiraiwa, C. J. Pan, et al., “ Correction of Glycogen Storage Disease Type 1a in a Mouse Model by Gene Therapy,” Journal of Biological Chemistry 275, no. 2 (2000): 828– 832, 10.1074/jbc.275.2.828. 10625614 · DOI
  16. [16]M. S. Sun, C. J. Pan, J. J. Shieh, et al., “ Sustained Hepatic and Renal Glucose‐6‐Phosphatase Expression Corrects Glycogen Storage Disease Type Ia in Mice,” Human Molecular Genetics 11, no. 18 (2002): 2155– 2164, 10.1093/hmg/11.18.2155. 12189168 · DOI
  17. [17]J. Y. Chou and B. C. Mansfield, “ Gene Therapy for Type I Glycogen Storage Diseases,” Current Gene Therapy 7, no. 2 (2007): 79– 88, 10.2174/156652307780363152. 17430128 PMC2553691 · DOI
  18. [18]A. Rossi, A. Venema, P. Haarsma, et al., “ A Prospective Study on Continuous Glucose Monitoring in Glycogen Storage Disease Type Ia: Toward Glycemic Targets,” Journal of Clinical Endocrinology and Metabolism 107, no. 9 (2022): e3612– e3623, 10.1210/clinem/dgac411. 35786777 PMC9387687 · DOI
  19. [19]F. Peeks, I. J. Hoogeveen, R. L. Feldbrugge, et al., “ A Retrospective In‐Depth Analysis of Continuous Glucose Monitoring Datasets for Patients With Hepatic Glycogen Storage Disease: Recommended Outcome Parameters for Glucose Management,” Journal of Inherited Metabolic Disease 44, no. 5 (2021): 1136– 1150, 10.1002/jimd.12383. 33834518 PMC8519135 · DOI
  20. [20]Y. T. Chen, M. Cornblath, and J. B. Sidbury, “ Cornstarch Therapy in Type I Glycogen‐Storage Disease,” New England Journal of Medicine 310, no. 3 (1984): 171– 175, 10.1056/NEJM198401193100306. 6581385 · DOI
  21. [21]S. W. Pipe, F. W. G. Leebeek, M. Recht, et al., “ Gene Therapy With Etranacogene Dezaparvovec for Hemophilia B,” New England Journal of Medicine 388, no. 8 (2023): 706– 718, 10.1056/NEJMoa2211644. 36812434 · DOI
  22. [22]F. Peeks, T. A. H. Steunenberg, F. de Boer, et al., “ Clinical and Biochemical Heterogeneity Between Patients With Glycogen Storage Disease Type IA: The Added Value of CUSUM for Metabolic Control,” Journal of Inherited Metabolic Disease 40, no. 5 (2017): 695– 702, 10.1007/s10545-017-0039-1. 28397058 PMC5579135 · DOI
  23. [23]Y. M. Lee, H. S. Jun, C. J. Pan, et al., “ Prevention of Hepatocellular Adenoma and Correction of Metabolic Abnormalities in Murine Glycogen Storage Disease Type Ia by Gene Therapy,” Hepatology 56, no. 5 (2012): 1719– 1729, 10.1002/hep.25717. 22422504 PMC3477505 · DOI
  24. [24]M. G. S. Rutten, T. G. J. Derks, N. C. A. Huijkman, et al., “ Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐Associated Protein 9‐Mediated Gene Editing,” Hepatology 74, no. 5 (2021): 2491– 2507, 10.1002/hep.32022. 34157136 PMC8597008 · DOI
  25. [25]K. J. Lei, L. L. Shelly, C. J. Pan, J. B. Sidbury, and J. Y. Chou, “ Mutations in the Glucose‐6‐Phosphatase Gene That Cause Glycogen Storage Disease Type 1a,” Science 262, no. 5133 (1993): 580– 583, 10.1126/science.8211187. 8211187 · DOI
  26. [26]K. J. Lei, C. J. Pan, L. L. Shelly, J. L. Liu, and J. Y. Chou, “ Identification of Mutations in the Gene for Glucose‐6‐Phosphatase, the Enzyme Deficient in Glycogen Storage Disease Type 1a,” Journal of Clinical Investigation 93, no. 5 (1994): 1994– 1999, 10.1172/JCI117192. 8182131 PMC294308 · DOI
  27. [27]A. C. Nathwani, E. G. Tuddenham, S. Rangarajan, et al., “ Adenovirus‐Associated Virus Vector‐Mediated Gene Transfer in Hemophilia B,” New England Journal of Medicine 365, no. 25 (2011): 2357– 2365, 10.1056/NEJMoa1108046. 22149959 PMC3265081 · DOI · Paper page
  28. [30]E. Tsalikian, P. Simmons, J. E. Gerich, C. Howard, and M. W. Haymond, “ Glucose Production and Utilization in Children With Glycogen Storage Disease Type I,” American Journal of Physiology 247, no. 4 Pt 1 (1984): E513– E519, 10.1152/ajpendo.1984.247.4.E513. 6388348 · DOI
  29. [31]W. F. Schwenk and M. W. Haymond, “ Optimal Rate of Enteral Glucose Administration in Children With Glycogen Storage Disease Type I,” New England Journal of Medicine 314, no. 11 (1986): 682– 685, 10.1056/NEJM198603133141104. 3081806 · DOI
  30. [32]B. Kalderon, S. H. Korman, A. Gutman, and A. Lapidot, “ Estimation of Glucose Carbon Recycling in Children With Glycogen Storage Disease: A 13C NMR Study Using [U‐13C]Glucose,” Proceedings of the National Academy of Sciences of the United States of America 86, no. 12 (1989): 4690– 4694, 10.1073/pnas.86.12.4690. 2734314 PMC287337 · DOI
  31. [33]K. I. Rother and W. F. Schwenk, “ Glucose Production in Glycogen Storage Disease I Is Not Associated With Increased Cycling Through Hepatic Glycogen,” American Journal of Physiology 269, no. 4 Pt 1 (1995): E774– E778, 10.1152/ajpendo.1995.269.4.E774. 7485494 · DOI
  32. [34]D. Weghuber, M. Mandl, M. Krssak, et al., “ Characterization of Hepatic and Brain Metabolism in Young Adults With Glycogen Storage Disease Type 1: A Magnetic Resonance Spectroscopy Study,” American Journal of Physiology. Endocrinology and Metabolism 293, no. 5 (2007): E1378– E1384, 10.1152/ajpendo.00658.2006. 17785500 · DOI
  33. [35]H. H. Huidekoper, G. Visser, M. T. Ackermans, H. P. Sauerwein, and F. A. Wijburg, “ A Potential Role for Muscle in Glucose Homeostasis: In Vivo Kinetic Studies in Glycogen Storage Disease Type 1a and Fructose‐1,6‐Bisphosphatase Deficiency,” Journal of Inherited Metabolic Disease 33, no. 1 (2010): 25– 31, 10.1007/s10545-009-9030-9. 20127282 PMC2828550 · DOI
  34. [36]B. S. Hijmans, A. Boss, T. H. van Dijk, et al., “ Hepatocytes Contribute to Residual Glucose Production in a Mouse Model for Glycogen Storage Disease Type Ia,” Hepatology 66, no. 6 (2017): 2042– 2054, 10.1002/hep.29389. 28727166 · DOI
  35. [38]S. N. DuBose, L. G. Kanapka, B. Bradfield, M. Sooy, R. W. Beck, and A. K. Steck, “ Continuous Glucose Monitoring Profiles in Healthy, Nondiabetic Young Children,” Journal of the Endocrine Society 6, no. 6 (2022): bvac060, 10.1210/jendso/bvac060. 35506147 PMC9049110 · DOI
  36. [39]J. Fernandes, R. Berger, and G. P. Smit, “ Lactate as a Cerebral Metabolic Fuel for Glucose‐6‐Phosphatase Deficient Children,” Pediatric Research 18, no. 4 (1984): 335– 339, 10.1203/00006450-198404000-00006. 6585774 · DOI

Cited by

Sorted by citations

Authors
Weinstein, D. A., Derks, T. G., Rodriguez‐Buritica, D. F., Ahmad, A., Couce, M., Mitchell, J. J., Riba‐Wolman, R., Mount, M., Sallago, J. B., Ross, K. M., van der Klauw, M. M., de Boer, F., van der Schaaf, C., Saavedra, H., Martínez‐Olmos, M., Atanga, E., Hosseini, A., Mitragotri, D., & Crombez, E.
Affiliations
  • University of Connecticut (US)
  • University Medical Center Groningen (NL)
  • Memorial Hermann (US)
  • University of Michigan (US)
  • Complejo Hospitalario Universitario de Santiago (ES)
  • Montreal Children's Hospital (CA)
  • Department of Endocrinology University of Groningen, University Medical Center Groningen Groningen the Netherlands
  • Section of Metabolic Diseases Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen Groningen the Netherlands
  • University Clinical Hospital of Santiago de Compostela, IDIS, CIBERER Santiago de Compostela Spain
  • Ultragenyx Pharmaceutical (United States) (US)
Corresponding author
Weinstein, David A.
ORCID
Venue
Journal of Inherited Metabolic Disease
Publisher
Wiley
Published
2025-03
Volume
48
Issue
2
Pages
e70014-e70014
ISSN
  • 0141-8955 (ISSN-L)
  • 1573-2665
DOI
10.1002/jimd.70014
PMC
PMC11893205
OpenAlex
W4408318778
Cited by
30
References
3
Citations by year
2026: 19 · 2025: 11
FWCI
17.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Inherited Metabolic Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
Ultragenyx Pharmaceutical
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
glycogen storage disease type Ia, AAV8 vector, gene therapy, glucose-6-phosphatase deficiency, liver-directed gene delivery, hypoglycemia, dose escalation, treatment safety, treatment efficacy
MeSH terms
Dependovirus, Adolescent, Adult, Female, Genetic Vectors, Glucose-6-Phosphatase, Glycogen Storage Disease Type I, Humans, Liver, Male, Middle Aged, Genetic Therapy, Treatment Outcome, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review