A gene therapy treatment that restores a missing liver enzyme in test animals could provide a cure for a rare metabolic disorder in humans.

People born with the disorder, called glycogen storage disease type Ia ( GSD-Ia ), can’t make an enzyme, glucose-6-phosphatase ( G6Pase ) that helps the liver store and release glucose.
Without treatment, their blood sugar levels drop dangerously low, causing seizures and organ damage.
Eating raw cornstarch, a slowly digested carbohydrate, and avoiding dietary sugar can help people with GSD-Ia maintain their glucose levels. However, even a special diet does not prevent the eventual liver damage that results from the absent enzyme, and many adults with the disease develop liver and kidney failure or liver cancer.
With treatment, most people with GSD-1a have a relatively normal lifespan.

The gene therapy developed at Duke would give liver cells the correct genetic code for manufacturing the enzyme. A modified virus transfers the enzyme genes by infecting liver cells. The virus, adeno-associated virus, is not linked to any known human disease, and cannot copy itself and spread to other people.

The research involved creating a virus so focused on targeting liver cells that only a tiny amount is needed for treatment, minimizing potential side effects. Showing that the virus is safe and effective in small doses is an important step in bringing the treatment to clinical trials in humans.

Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver.
Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor in GSD-Ia mice.

These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector–mediated gene therapy for GSD-Ia.

GSD-Ia occurs in about one of every 100,000 births in the U.S. Duke is treating about 100 patients with the disease.

A long-term study would demonstrate whether gene therapy can prevent complications such as kidney failure and liver cancer, which develop even if people strictly control their diet and blood sugar levels. Other problems associated with the disease include growth restriction, high blood pressure, pancreatitis and persistent hypoglycemia.

Source: Duke University Medical Center, 2008

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