Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia

Crane, B; Luo, Xunrong; Demaster, A; Williams, Kyha D.; Kozink, Daniel M.; Zhang, P; Brown, T. T.; Pinto, Carlos; Oka, Koichiro; Sun, Francis; Jackson, Mark W.; Chan, Lawrence; Koeberl, Dwight D.

doi:10.1038/gt.2011.86

Cited by 21 publications

(22 citation statements)

References 31 publications

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“…The slightly elevated tranaminase levels observed in other dogs were consistent with the mild liver toxicity observed in dogs with GSD-Ia (Crane et al, 2011). Renal failure is associated with elevated serum creatinine in dogs with GSD-Ia (Crane et al, 2011). Serum creatinine was elevated only at one instance in Dog R, and it normalized after fluid and dietary therapy were administered (Fig.…”

Section: Residual Hepatorenal Involvement Persisted Despite Biochemicsupporting

confidence: 79%

“…However, AST was not elevated in Dog T at 5.5 months of age, which was 4 weeks following AAV2/1 vector administration. The slightly elevated tranaminase levels observed in other dogs were consistent with the mild liver toxicity observed in dogs with GSD-Ia (Crane et al, 2011). Renal failure is associated with elevated serum creatinine in dogs with GSD-Ia (Crane et al, 2011).…”

Section: Residual Hepatorenal Involvement Persisted Despite Biochemicsupporting

confidence: 78%

“…Breeding and neonatal care of puppies, vector administration, and monitoring Genetic analysis, vector administration to affected puppies via jugular venipuncture at 2 or 3 days of age, and subsequent feeding and monitored were performed as described by Crane et al (2011). Following weaning, dogs were fed and monitored three times daily.…”

Section: Methodsmentioning

confidence: 99%

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Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia

et al. 2012

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Glycogen storage disease type Ia (GSD-Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), primarily found in liver and kidney, which causes life-threatening hypoglycemia. Dogs with GSD-Ia were treated with double-stranded adeno-associated virus (AAV) vectors encoding human G6Pase. Administration of an AAV9 pseudotyped (AAV2/9) vector to seven consecutive GSD-Ia neonates prevented hypoglycemia during fasting for up to 8 hr; however, efficacy eventually waned between 2 and 30 months of age, and readministration of a new pseudotype was eventually required to maintain control of hypoglycemia. Three of these dogs succumbed to acute hypoglycemia between 7 and 9 weeks of age; however, this demise could have been prevented by earlier readministration an AAV vector, as demonstrated by successful prevention of mortality of three dogs treated earlier in life. Over the course of this study, six out of nine dogs survived after readministration of an AAV vector. Of these, each dog required readministration on average every 9 months. However, two were not retreated until >34 months of age, while one with preexisting antibodies was re-treated three times in 10 months. Glycogen content was normalized in the liver following vector administration, and G6Pase activity was increased in the liver of vector-treated dogs in comparison with GSD-Ia dogs that received only with dietary treatment. G6Pase activity reached approximately 40% of normal in two female dogs following AAV2/9 vector administration. Elevated aspartate transaminase in absence of inflammation indicated that hepatocellular turnover in the liver might drive the loss of vector genomes. Survival was prolonged for up to 60 months in dogs treated by readministration, and all dogs treated by readministration continue to thrive despite the demonstrated risk for recurrent hypoglycemia and mortality from waning efficacy of the AAV2/9 vector. These preclinical data support the further translation of AAV vector-mediated gene therapy in GSD-Ia.

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Section: Residual Hepatorenal Involvement Persisted Despite Biochemicsupporting

confidence: 79%

Section: Residual Hepatorenal Involvement Persisted Despite Biochemicsupporting

confidence: 78%

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Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia

et al. 2012

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“…The initial HDAd vector was serotype 5, and the dog was successfully retreated with the serotype 2 HDAd vector for an additional 12 months before developing recurrent hypoglycemia. Another GSD Ia dog treated with both serotype 5 and 2 HDAd vectors survived until 12 months of age and then was euthanized as a result of renal complications associated with GSD Ia, which were not reversed by HDAd-mediated gene therapy (Crane et al 2012). …”

Section: Development Of Gene Therapy For Gsd Ia In the Canine Modelmentioning

confidence: 99%

Large animal models and new therapies for glycogen storage disease

Brooks

Koeberl

2014

J of Inher Metab Disea

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Glycogen storage diseases (GSD), a unique category of inherited metabolic disorders, were first described early in the 20th century. Since then, the biochemical and genetic bases of these disorders have been determined, and an increasing number of animal models for GSD have become available. At least 7 large mammalian models have been developed for laboratory research on GSDs. These models have facilitated the development of new therapies, including gene therapy, which are undergoing clinical translation. For example, gene therapy prolonged survival and prevented hypoglycemia during fasting for greater than one year in dogs with GSD type Ia, and the need for periodic re-administration to maintain efficacy was demonstrated in that dog model. The further development of gene therapy could provide curative therapy for patients with GSD and other inherited metabolic disorders.

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“…The degree of G6Pase expression needed to prevent the formation of liver adenomas remains to be deterimined. One dog with GSD-Ia developed an adenoma in the setting of <20% G6Pase activity as determined from GSD-Ia carriers, which corresponds to approximately 10% of normal G6Pase activity in liver (Crane et al 2011).…”

Section: Introductionmentioning

confidence: 99%

In search of proof‐of‐concept: gene therapy for glycogen storage disease type Ia

Koeberl

2012

J of Inher Metab Disea

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The emergence of life threatening long-term complications in glycogen storage disease type Ia (GSD-Ia) has emphasized the need for new therapies, such as gene therapy, which could achieve biochemical correction of glucose-6-phosphatase deficiency and reverse clinical involvement. We have developed gene therapy with a novel adeno-associated virus (AAV) vector that: 1) prevented mortality and corrected glycogen storage in the liver, 2) corrected hypoglycemia during fasting, and 3) achieved efficacy with a low number of vector particles in G6Pase-deficient mice and dogs. However, the gradual loss of transgene expression from episomal AAV vector genomes eventually necessitated the administration of a different pseudotype of the AAV vector to sustain dogs with GSD-Ia. Further preclinical development of AAV vector-mediated gene therapy is therefore warranted in GSD-Ia.

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Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia

Cited by 21 publications

References 31 publications

Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia

Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia

Large animal models and new therapies for glycogen storage disease

In search of proof‐of‐concept: gene therapy for glycogen storage disease type Ia

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