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Dwight Koeberl

Clinical Sciences
Research Interest: 
Research Summary: 
Developement of new therapy for genetic diseases
Research Description: 

The focus of our research has been the development of new therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body: glucose-6-phosphatase (G6Pase) in GSD type Ia (GSD-Ia) and acid a-glucosidase (GAA) in GSD type II (Pompe disease). G6Pase deficiency in GSD-Ia affects primarily liver and kidney, while GAA deficiency in Pompe disease causes primarily muscle disease. We have developed gene therapy with viral vectors, including adeno-associated virus (AAV) vectors and adenovirus vectors. AAV vectors that were pseudotyped with alternative AAV serotypes, such as AAV8, demonstrated enhanced tropism for target tissues, including the liver, heart, and skeletal muscle, in animal models for GSD.

We have recently evaluated the efficacy of an AAV vector encoding G6Pase in mice and dogs with GSD-Ia with regard to the prevention of hypoglycemia during prolonged fasting and the prevention of long-term complications of GSD-Ia including renal dysfunction. The AAV vector in question is being considered for a Phase I clinical trial in adults with GSD-Ia.

In Pompe disease we demonstrated that liver-restricted expression with an AAV vector prevented antibody responses in GAA-knockout mice by inducing immune tolerance to human GAA. Antibody responses have complicated enzyme replacement therapy for Pompe disease and emphasized a potential advantage of gene therapy for this disorder. The strategy of administering low-dose gene therapy prior to initiation of enzyme replacement therapy, termed immunomodulatory gene therapy, prevented antibody formation and increased efficacy in Pompe disease mice. Consequently we are planning clinical trials of immunomodulatory gene therapy in patients with Pompe disease, who might not otherwise respond to enzyme replacement therapy.

Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance.
Sun B, Bird A, Young SP, Kishnani PS, Chen YT, Koeberl DD.
Am J Hum Genet. 2007. 81:1042-9.

AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia.
Koeberl DD, Pinto C, Sun B, Li S, Kozink DM, Benjamin DK, Demaster AK, Kruse MA, Vaughn V, Hillman S, Bird A, Jackson M, Brown T, Kishnani PS, Chen YT.
Mol Ther. 2008. 16:665-72.

Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease.
Sun B, Kulis MD, Young SP, Hobeika AC, Li S, Bird A, Zhang H, Li Y, Clay TM, Burks W, Kishnani PS, Koeberl DD.
Mol Ther. 2010. 18:353-60.

Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.
Koeberl DD, Luo X, Sun B, McVie-Wylie A, Dai J, Li S, Banugaria SG, Chen YT, Bali DS.
Mol Genet Metab. 2011. 103:107-12.

Hepatorenal Correction in Murine Glycogen Storage Disease Type I With a Double-stranded Adeno-associated Virus Vector.
Luo X, Hall G, Li S, Bird A, Lavin PJ, Winn MP, Kemper AR, Brown TT, Koeberl DD.
Mol Ther. 2011. 19:1961-70.