Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 977–984 | Cite as

Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia

  • Young Mok Lee
  • Thomas J. Conlon
  • Andrew Specht
  • Kirsten E. Coleman
  • Laurie M. Brown
  • Ana M. Estrella
  • Monika Dambska
  • Kathryn R. Dahlberg
  • David A. WeinsteinEmail author
Glycogen Storage Disease



Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy.


A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed.


Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2–4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose.


rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.



The authors gratefully acknowledge the University of Florida GSD Puppy Care Team and the University of Florida Animal Care Services and College of Veterinary Medicine Veterinary Staff for their assistance in animal care. The authors also thank and acknowledge Dr. Catherine Mah. Dr. John Verstegen, Dr. Maggie Struck, Ms. Catherine Correia, Dr. Barry Byrne and Mr. Travis Cossette for their efforts to get this work started. Mr. Noah Drazen is recognized for his assistance in preparing this manuscript.


This research was made possible grant support provided by the Global Center for GSD, the Children’s Fund for GSD Research, Children’s Miracle Network, and the National Institutes of Health (NHLBI P01 HL59412-06 and NIDDK P01 DK58327-03). Philanthropic support was also proved by the Fry Family Foundation and the following funds managed through the University of Florida Office of Development: Scott Miller GSD Program Fund, Matthew Ehrman GSD Research Fund, Jonah Pournazarian GSD Ib Research Fund, GSD Dream Fund, Green Family Fund for GSD Research, Canadian Fund for the Cure of GSD, Team Tallulah for Type Ib Research, and Jamie Konieczka Type Ib GSD Research Fund.

Compliance with ethical standards

These investigations were approved by and performed in accordance with the guidelines of the University of Florida Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10545_2018_199_MOESM1_ESM.docx (169 kb)
Supplement figure 1 Biochemical Characteristics Over Time (additional values). Serum analysis for Total Biliruvin, Total Protein, Albumin, Globulin, Calcium, Phosphorus, Magnesium, Sodium, Potassium, Chloride, Total CO2 and Anion Gap. Black line with round symbol (CO), Red line with square symbol (GE), Blue line with triangle (TU) and Purple line with reversed triangle (JA). Area between dashed line indicates normal ranges of the enzymes or blood metabolites (DOCX 168 kb)


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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Young Mok Lee
    • 1
    • 2
  • Thomas J. Conlon
    • 3
    • 4
  • Andrew Specht
    • 5
  • Kirsten E. Coleman
    • 3
  • Laurie M. Brown
    • 2
  • Ana M. Estrella
    • 1
    • 2
  • Monika Dambska
    • 2
    • 6
  • Kathryn R. Dahlberg
    • 6
  • David A. Weinstein
    • 1
    • 2
    • 6
    Email author
  1. 1.Glycogen Storage Disease Program, Department of PediatricsUniversity of Connecticut School of MedicineFarmingtonUSA
  2. 2.Glycogen Storage Disease ProgramUniversity of Florida College of MedicineGainesvilleUSA
  3. 3.Powell Gene Therapy CenterUniversity of FloridaGainesvilleUSA
  4. 4.CR Scientific and Compliance ConsultingLLCGainesvilleUSA
  5. 5.Department of Small Animal Clinical SciencesUniversity of Florida College of Veterinary MedicineGainesvilleUSA
  6. 6.Glycogen Storage Disease ProgramConnecticut Children’s Medical CenterHartfordUSA

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