Gene therapy for GSD-1a

Posted by & filed under Part 07: CARBOHYDRATES.

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.
Koeberl DD, Sun BD, Damodaran TV, Brown T, Millington DS, Benjamin DK, Bird A,
Schneider A, Hillman S, Jackson M, Beaty RM, Chen YT.
Gene Ther. 2006 May 4

This group describes the IV administration of a pseudotyped AAV8 vector for the correction of glycogen storage disease 1a in a mouse model. Partial biochemical correction was sustained up to 7 months after the administration.

For more information on GSD-1a, please see chapter 71.

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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

One Response to “Gene therapy for GSD-1a”

  1. pcampeau



    The treatment of type I glycogen storage disease is to maintain normal blood glucose concentrations. Normoglycemia can correct most of the metabolic abnormalities and will reduce the morbidity associated with this disease. Normoglycemia can be achieved through a number of different approaches, including total parenteral nutrition, nocturnal nasogastric infusion of glucose,244 and orally administered uncooked cornstarch.245 The result of long-term treatment data are now available for the latter two dietary regimens;170,246,246a both methods have yielded dramatic clinical improvement in these patients (see Prognosis below). Nocturnal nasogastric drip feeding can be introduced in early infancy from the time of diagnosis. It may consist of an elemental enteral formula, or it may contain only glucose or glucose polymer to provide 8 to 10 mg/kg/min of glucose in an infant, and 5 to 7 mg/kg/min in an older child.163,247 Frequent feedings with a high complex carbohydrate content are given during the day. The distribution of calories should be approximately 65 to 70 percent carbohydrate, 10 to 15 percent protein, and 20 to 25 percent fat with one-third of the total 24-h caloric intake provided through nocturnal gastric feeding. If nocturnal nasogastric infusion is being used, the first meal of the day should be taken no longer than 15 to 30 min after stopping the infusion. Continuous feeding with infusion pump should be used with meticulous attention to detail, as hypoglycemia and death have resulted from malfunction of the pump or disconnection of the tube.248,249

    Uncooked cornstarch acts as a slow-release form of glucose, and can be introduced at a dose of 1.6 g/kg every 4 h for infants under 2 years of age.250 The response of young infants is variable. As the child grows older, the cornstarch regimen can be changed to every 6 h, and cornstarch can be prepared in water or diet drinks (1:2, weight in gram:volume in ml) at a dose of 1.75 to 2.5 g/kg of body weight. In young adults, a single dose of cornstarch at bedtime can maintain normoglycemia for greater than 7 h in most patients.251 The caloric distributions with cornstarch therapy are similar to those in patients receiving gastric feeding.

    Dietary intake of fructose and galactose should be restricted, as it cannot be converted to free glucose. As the diet is restricted, dietary supplements of multivitamins and calcium are required. Allopurinol is used to help reduce the levels of uric acid. The aim is to lower the serum urate concentration to below 6.4 mg/dl, the concentration at which monosodium urate saturates extracellular fluids.252

    In type Ib glycogen storage disease, granulocyte and granulocyte-macrophage colony-stimulating factors have been used successfully to correct the neutropenia, to decrease the number and the severity of bacterial infections, and to improve the chronic inflammatory bowel disease in these patients.253,254

    Portacaval shunts have been performed with limited benefit for patients with type I glycogen storage disease.255,256 The shunt did not alter the metabolic status or the consequences of the abnormalities in the patients undergoing the procedures. Because good dietary management reduces or prevents most of the complications of type I glycogen storage disease, portacaval shunts should not be performed.

    Liver transplantation has been performed in patients with type I disease because of multiple liver adenomas bearing the risk of malignant transformation and/or poor metabolic control. None, however, had carcinomas confirmed in the explanted livers (see references 257 and 257a). The hypoglycemia and other biochemical abnormalities were corrected after transplantation; and growth improved. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in type Ib patients after liver transplantation, necessitating continuous treatment with granulocyte colony-stimulating factor. In view of the favorable response to the conventional treatment, liver transplantation should be considered only after all other methods of dietary treatment have failed, or when there is evidence of hepatocellular carcinomas.

    Kidney transplantation has been performed secondary to renal failure. The renal allografts did not correct the hypoglycemia.258,259 In one patient, the posttransplantation course was complicated by increased lactic acidemia, hyperlipidemia, and hyperglycemia.259 Insulin resistance was also found. The increase in lactate production was thought to be the result of the gluconeogenic effect of the glucocorticoids, which were given for immunosuppression.

    Surgery in type I glycogen storage disease should not be undertaken without first evaluating the patient’s bleeding status and establishing good metabolic control. Prolonged bleeding time can be normalized by the use of intensive intravenous glucose infusion for 24 to 48 h prior to surgery. Use of 1-deamino-8-D-arginine vasopressin DDAVP was reported to reduce bleeding complications.260 Lactated Ringer’s solution should be avoided as it contains lactate and no glucose. Glucose levels should be maintained in the normal range throughout surgery with the use of 10 percent dextrose.

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