Prevention of complications in glycogen storage disease type Ia with optimization of metabolic control

Abstract

Prior to 1971, type Ia glycogen storage disease was marked by life-threatening hypoglycemia, lactic acidosis, severe failure to thrive, and developmental delay. With the introduction of continuous feeds in the 1970s and cornstarch in the 1980s, the prognosis improved, but complications almost universally developed. Changes in the management of type Ia glycogen storage disease have resulted in improved metabolic control, and this manuscript reviews the increasing evidence that complications can be delayed or prevented with optimal metabolic control as previously was seen in diabetes.

Gene therapy prevents hepatic tumor initiation in murine glycogen storage disease type Ia at the tumor‐developing stage

“…Studies have shown that HCA formation in GSD‐I is impacted by metabolic controls . Wang et al showed that a lower rate of HCA formation correlated with good metabolic controls that reduce triglyceride concentrations in GSD‐Ia patients.…”

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

“…There is increasing evidence that liver and kidney complications in glycogen storage disease are almost universal in mice (Mutel et al 2011;Clar et al 2014) and humans with poor metabolic control (Rake et al, 2002). Improved metabolic control, however, has been associated with fewer liver and kidney complications in humans with GSD-Ia (Wang et al 2011;Okechuku et al, 2017;Dambska et al, 2017). Animal studies have provided clues regarding the enzyme activity required to prevent hypoglycemia and complications in GSD-Ia.…”

“…Renal disease has developed in patients with GSD-Ia who have undergone liver transplantation, but this could be related to the use of nephrotoxic immunosuppression (Davis and Weinstein 2008;Reddy et al 2009). In contrast, recent investigations have demonstrated that kidney disease can be prevented or reversed with good metabolic control (Okechuku et al 2017;Dambska et al, 2017). The improved metabolic control in the dogs may explain the lack of renal complications, but humans will need to be followed extremely closely after any gene therapy trial using AAV to ensure that kidney disease does not develop.…”

Response letter

“…We appreciate the comments and thoughts regarding gene therapy in the naturally occurring canine model of glycogen storage disease type Ia (GSD-Ia). We agree that nutritional therapy can prevent complications in humans with GSD-Ia (Dambska et al 2017), but nutritional therapy by itself did not prevent complications in our dogs. It is, therefore, critical not to minimize the contribution from the gene therapy, especially since there is good evidence in the murine model that rAAV-mediated gene therapy can prevent hepatocellular adenoma/carcinoma (HCA/HCC) formation if adequate hepatic glucose-6-phosphatase-α (G6Pase-α) enzymatic activity was obtained (Lee et al 2012;Kim et al 2017).…”