Dwight D. Koeberl, MD, PhD

Department / Division:
Pediatrics / Medical Genetics

Address:
DUMC 3528
Durham, NC 27710

Appointment Telephone:
919-684-2036

Office Telephone:
919-681-9919

Fax Telephone:
919-684-2362

• MD, PhD, Mayo Medical School (Minnesota), 1990

• Pediatrics, University of California, San Francisco Hospitals, 1990-1992

• Clinical Genetics, University of Washington, 1993-1996
• Biochemical Genetics, University of Washington, 1996-1998

Clinical Interests:
Genetic disorders including metabolic disorders and syndromes, evaluation of children with growth failure or developmental delay, treatment of inherited disorders of metabolism, especially by enzyme replacement or gene therapy

Research Interests:
The focus of research in my laboratory has been gene therapy with viral vectors, including adeno-associated virus (AAV) vectors and adenovirus vectors.  AAV vectors have been pseudotyped with alternative AAV serotypes to enhance tropism for target tissues, including the liver, heart, and skeletal muscle.  Pseudotyped AAV vectors enhanced gene transfer in the knockout mouse models for 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-Ia (von Gierke disease) and acid α-glucosidase (GAA) in GSD-II (Pompe disease).  G6Pase deficiency in GSD-Ia affects primarily liver and kidney, while GAA deficiency in GSD-II causes primarily muscle disease.  AAV vectors transduced liver and striated muscle to replace the deficient enzyme in GSD-Ia and GSD-II mice, subsequently demonstrating efficacy through reduction in glycogen storage and correction of associated biomarkers.  

Summarizing highlights of our research over the past several years:
1) GSD-Ia: Early mortality complicates research with both the murine and canine models of GSD-Ia.  We prolonged survival and reversed the biochemical abnormalities in GSD-Ia mice (1).  Recently we effectively treated GSD-Ia dogs and mice, demonstrating efficacy during a one year follow-up period (5).
2) GSD-II/Pompe disease:  Successful gene therapy in GSD-II mice required the evasion of immune responses to introduced GAA; importantly, immune responses complicated enzyme replacement therapy for GSD-II and emphasized the need for gene therapy.  We evaded immune responses to introduced GAA by liver-restricted expression with an AAV vector, demonstrating the ability to achieve efficacy by inducing tolerance to human GAA (2,4).  
3) Phenylketonuria/PKU: We demonstrated long-term biochemical correction of PKU in mice with an AAV2/8 vector, which is a very significant disorder detected by newborn screening and currently inadequately treated by dietary therapy (3).  Phenylalanine levels in mice were corrected in the blood, and elevated phenylalanine causes mental retardation and birth defects in children born to affected women.

References
1)Koeberl DD, Sun BD, Damodaran TV, Brown T, Millington DS, Benjamin DK Jr., et al. (2006) Early, sustained efficacy of AAV vector-mediated gene therapy in glycogen storage disease type Ia.  Gene Ther 13,1281-1289.
2)Franco LM, Sun B, Yang X, Bird A, Zhang H, Schneider A, Amalfitano A, Chen YT, Koeberl DD. (2005) Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II. Mol. Ther., 12, 876-884.
3)Harding CO, Gillingham MB, Hamman K, Clark H, Goebel-Daghighi E, Bird A Koeberl DD. (2006) Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. Gene Ther., 13, 457-462.
4)Sun B, Bird A, Young SP, Kishnani PS, Chen YT, Koeberl DD. (2007) Enhanced response to enzyme replacement therapy in Pompe disease following the induction of immune tolerance.  Am. J. Hum. Genet., 81, 1042-49.
5)Koeberl DD, Pinto C, Sun B, Li S, Kozink DM, Benjamin DK Jr, et al. (2008) AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Mol Ther, 16, 665-72.

Representative Publications:
Koeberl DD, Pinto C, Sun B, Li S, Kozink DM, Benjamin DK Jr, Demaster AK, Kruse MA, Vaughn V, Hillman S, Bird A, Jackson M, Brown T, Kishnani PS, Chen YT. AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia.  Mol Ther.  2008 Apr;16(4):665-72. (2008) Abstract

Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, Goodman SI, Harding C, Kahler S, Kronn D, Longo N. A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.  Mol Genet Metab.  2008 Apr;93(4):363-70. (2008) Abstract

Sun B, Bird A, Young SP, Kishnani PS, Chen YT, Koeberl DD. Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance.  Am J Hum Genet.  2007 Nov;81(5):1042-9. (2007) Abstract

Koeberl DD, Sun B, Bird A, Chen YT, Oka K, Chan L. Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia.  Mol Ther.  2007 Jul;15(7):1253-8. (2007) Abstract

Koeberl DD, Kishnani PS, Chen YT. Glycogen storage disease types I and II: Treatment updates. J Inherit Metab Dis. 2007 Feb 16. (2007) Abstract

Sun B, Zhang H, Benjamin DK Jr, Brown T, Bird A, Young SP, McVie-Wylie A, Chen YT, Koeberl DD. Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II.  Mol Ther.  2006 Dec;14(6):822-30. (2006) Abstract

Koeberl DD. Vector-related tumorigenesis not found in ornithine transcarbamylase-deficient mice. Mol Ther. 2006 Jul;14(1):1-2. (2006) Abstract

Koeberl DD, Sun BD, Damodaran TV, Brown T, Millington DS, Benjamin DK Jr, Bird A, Schneider A, Hillman S, Jackson M, Beaty RM, Chen YT. Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia.  Gene Ther.  2006 Oct;13(19):1430. (2006) Abstract

Harding CO, Gillingham MB, Hamman K, Clark H, Goebel-Daghighi E, Bird A, Koeberl DD. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria.  Gene Ther.  2006 Mar;13(5):457-62. (2006) Abstract

Sun B, Zhang H, Franco LM, Young SP, Schneider A, Bird A, Amalfitano A, Chen YT, Koeberl DD. Efficacy of an adeno-associated virus 8-pseudotyped vector in glycogen storage disease type II. Mol Ther. 2005 Jan;11(1):57-65. (2005) Abstract

Sun B, Zhang H, Franco LM, Brown T, Bird A, Schneider A, Koeberl DD. Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter. Mol Ther. 2005 Jun;11(6):889-98. (2005) Abstract

Franco LM, Sun B, Yang X, Bird A, Zhang H, Schneider A, Brown T, Young SP, Clay TM, Amalfitano A, Chen YT, Koeberl DD. Evasion of Immune Responses to Introduced Human Acid alpha-Glucosidase by Liver-Restricted Expression in Glycogen Storage Disease Type II. Mol Ther. 2005 Jul 5. (2005) Abstract

Sun B, Chen YT, Bird A, Xu F, Hou YX, Amalfitano A, Koeberl DD. Packaging of an AAV vector encoding human acid alpha-glucosidase for gene therapy in glycogen storage disease type II with a modified hybrid adenovirus-AAV vector. Mol Ther. 2003 Apr;7(4):467-77. (2003) Abstract

Sun B, Chen YT, Bird A, Amalfitano A, Koeberl DD. Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV vector. Mol Ther. 2003 Feb;7(2):193-201. (2003) Abstract

Koeberl DD, Young SP, Gregersen NS, Vockley J, Smith WE, Benjamin DK Jr, An Y, Weavil SD, Chaing SH, Bali D, McDonald MT, Kishnani PS, Chen YT, Millington DS. Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res. 2003 Aug;54(2):219-23. (2003) Abstract

Beaty RM, Jackson M, Peterson D, Bird A, Brown T, Benjamin DK Jr, Juopperi T, Kishnani P, Boney A, Chen YT, Koeberl DD. Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. Gene Ther. 2002 Aug;9(15):1015-22. (2002) Abstract

Smith WE, Millington DS, Koeberl DD, Lesser PS. Glutaric acidemia, type I, missed by newborn screening in an infant with dystonia following promethazine administration. Pediatrics. 2001 May;107(5):1184-7. (2001) Abstract

Koeberl DD, Bonham L, Halbert CL, Allen JM, Birkebak T, Miller AD. Persistent, therapeutically relevant levels of human granulocyte colony-stimulating factor in mice after systemic delivery of adeno-associated virus vectors. Hum Gene Ther. 1999 Sep 1;10(13):2133-40. (1999) Abstract

Koeberl DD, Alexander IE, Halbert CL, Russell DW, Miller AD. Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1426-31. (1997) Abstract

Koeberl DD, McGillivray B, Sybert VP. Prenatal diagnosis of 45,X/46,XX mosaicism and 45,X: implications for postnatal outcome. Am J Hum Genet. 1995 Sep;57(3):661-6. (1995) Abstract

Koeberl DD, Bottema CD, Ketterling RP, Bridge PJ, Lillicrap DP, Sommer SS. Mutations causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene. Am J Hum Genet. 1990 Aug;47(2):202-17. (1990) Abstract

Koeberl DD, Bottema CD, Buerstedde JM, Sommer SS. Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG. Am J Hum Genet. 1989 Sep;45(3):448-57. (1989) Abstract

Bottema CD, Koeberl DD, Sommer SS. Direct carrier testing in 14 families with haemophilia B. Lancet. 1989 Sep 2;2(8662):526-9. (1989) Abstract

Stoflet ES, Koeberl DD, Sarkar G, Sommer SS. Genomic amplification with transcript sequencing. Science. 1988 Jan 29;239(4839):491-4. (1988) Abstract