Dwight D. Koeberl, MD, PhD



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Professor of Pediatrics
Professor in Molecular Genetics and Microbiology
Department / Division:
Pediatrics / Pediatrics-Medical Genetics
DUMC 103856
Durham, NC 27710
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  • 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, mitochondrial disorders and syndromes; biochemical and metabolic testing; evaluation of children with growth failure or developmental delay; treatment of inherited disorders of metabolism, especially by enzyme replacement or gene therapy; newborn screening
Research Interests:
The focus of our research has been the development of gene therapy with  adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 
1) GSD type Ia: Glucose-6-phosphatase (G6Pase) deficient animals provide models for developing new therapy for GSD type Ia, although early mortality complicates research with both the murine and canine models of GSD Ia. We have prolonged the survival and reversed the biochemical abnormalities in G6Pase-knockout mice and dogs with GSD type Ia, following the administration of AAV8-pseudotyped AAV vectors encoding human G6Pase. More recently, we have performed genome editing to integrate a therapeutic transgene in a safe harbor locus for mice with GSD Ia, permanently correcting G6Pase deficiency in the GSD Ia liver. Finally, we have identified reduced autophagy as an underlying hepatocellular defect that might be treated with pro-autophagic drugs in GSD Ia.
2) GSD II/Pompe disease: Pompe disease is caused by the deficiency of acid-alpha-glucosidase (GAA) in muscle, resulting in the massive accumulation of lysosomal glycogen in striated muscle with accompanying weakness. While enzyme replacement has shown promise in infantile-onset Pompe disease patients, no curative therapy is available. We demonstrated that AAV vector-mediated gene therapy will likely overcome limitations of enzyme replacement therapy, including formation of anti-GAA antibodies and the need for frequent infusions. 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. Furthermore, we have developed drug therapy to increase the receptor-mediated uptake of GAA in muscle cells, which provides adjunctive therapy to more definitively treat Pompe disease.
3) PKU: We demonstrated long-term biochemical correction of PKU in mice with an AAV8 vector. PKU is a very significant disorder detected by newborn screening and currently inadequately treated by dietary therapy. Phenylalanine levels in mice were corrected in the blood, and elevated phenylalanine causes mental retardation and birth defects in children born to affected women, and gene therapy for PKU would address an unmet need for therapy in this disorder.
Representative Publications:
  • Farah, BL; Landau, DJ; Sinha, RA; Brooks, ED; Wu, Y; Fung, SY; Tanaka, T; Hirayama, M; Bay, BH; Koeberl, DD; Yen, PM. Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. Journal of Hepatology. 2016;64:370-379.  Abstract
  • Han, SO; Pope, R; Li, S; Kishnani, PS; Steet, R; Koeberl, DD. A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease. Molecular Genetics and Metabolism. 2016;117:114-119.  Abstract
  • Landau, DJ; Brooks, ED; Perez-Pinera, P; Amarasekara, H; Mefferd, A; Li, S; Bird, A; Gersbach, CA; Koeberl, DD. In Vivo Zinc Finger Nuclease-mediated Targeted Integration of a Glucose-6-phosphatase Transgene Promotes Survival in Mice With Glycogen Storage Disease Type IA. Molecular Therapy. 2016;24:697-706.  Abstract
  • McGarrah, RW; Ahmad, T; Koeberl, DD; Patel, CB. The heart is just a muscle. Circulation. 2015;131:914-922.  Abstract
  • Mori, M; Goldstein, J; Young, SP; Bossen, EH; Shoffner, J; Koeberl, DD. Complex III deficiency due to an in-frame MT-CYB deletion presenting as ketotic hypoglycemia and lactic acidosis. Molecular Genetics and Metabolism Reports. 2015;4:39-41.  Abstract
  • Sun, B; Brooks, ED; Koeberl, DD. Preclinical Development of New Therapy for Glycogen Storage Diseases. Current gene therapy. 2015;15:338-347.  Abstract
  • Wang, G; Young, SP; Bali, D; Hutt, J; Li, S; Benson, J; Koeberl, DD. Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Molecular Therapy - Methods and Clinical Development. 2014;1:14018.  Abstract
  • Brooks, ED; Little, D; Arumugam, R; Sun, B; Curtis, S; Demaster, A; Maranzano, M; Jackson, MW; Kishnani, P; Freemark, MS; Koeberl, DD. Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia. Molecular Genetics and Metabolism. 2013;109:161-170.  Abstract
  • Li, S; Sun, B; Nilsson, MI; Bird, A; Tarnopolsky, MA; Thurberg, BL; Bali, D; Koeberl, DD. Adjunctive ß2-agonists reverse neuromuscular involvement in murine Pompe disease. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013;27:34-44.  Abstract
  • Demaster, A; Luo, X; Curtis, S; Williams, KD; Landau, DJ; Drake, EJ; Kozink, DM; Bird, A; Crane, B; Sun, F; Pinto, CR; Brown, TT; Kemper, AR; Koeberl, DD. Long-term efficacy following readministration of an adeno-associated virus vector in dogs with glycogen storage disease type Ia. Human Gene Therapy. 2012;23:407-418.  Abstract
  • Zhang, P; Sun, B; Osada, T; Rodriguiz, R; Yang, XY; Luo, X; Kemper, AR; Clay, TM; Koeberl, DD. Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. Human Gene Therapy. 2012;23:460-472.  Abstract
  • Luo, X; Hall, G; Li, S; Bird, A; Lavin, PJ; Winn, MP; Kemper, AR; Brown, TT; Koeberl, DD. Hepatorenal correction in murine glycogen storage disease type I with a double-stranded adeno-associated virus vector. Molecular Therapy. 2011;19:1961-1970.  Abstract
  • Sun, B; Kulis, MD; Young, SP; Hobeika, AC; Li, S; Bird, A; Zhang, H; Li, Y; Clay, TM; Burks, W; Kishnani, PS; Koeberl, DD. Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine pompe disease. Molecular Therapy. 2010;18:353-360.  Abstract
  • Koeberl, DD; Kishnani, PS; Bali, D; Chen, YT. Emerging therapies for glycogen storage disease type I. Trends in Endocrinology and Metabolism. 2009;20:252-258.  Abstract
  • Sun, B; Li, S; Yang, L; Damodaran, T; Desai, D; Diehl, AM; Alzate, O; Koeberl, DD. Activation of glycolysis and apoptosis in glycogen storage disease type Ia. Molecular Genetics and Metabolism. 2009;97:267-271.  Abstract
  • Sun, B; Zhang, H; Bird, A; Li, S; Young, SP; Koeberl, DD. Impaired clearance of accumulated lysosomal glycogen in advanced Pompe disease despite high-level vector-mediated transgene expression. The Journal of Gene Medicine. 2009;11:913-920.  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. Molecular Genetics and Metabolism. 2008;93:363-370.  Abstract
  • 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. AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Molecular Therapy. 2008;16:665-672.  Abstract
  • Sun, B; Young, SP; Li, P; Di, C; Brown, T; Salva, MZ; Li, S; Bird, A; Yan, Z; Auten, R; Hauschka, SD; Koeberl, DD. Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy. Molecular Therapy. 2008;16:1366-1371.  Abstract
  • Koeberl, DD; Kishnani, PS; Chen, YT. Glycogen storage disease types I and II: treatment updates. Journal of Inherited Metabolic Disease. 2007;30:159-164.  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. Molecular Therapy. 2007;15:1253-1258.  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. The American Journal of Human Genetics. 2007;81:1042-1049.  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 Therapy. 2006;13:457-462.  Abstract
  • Koeberl, DD. Vector-related tumorigenesis not found in ornithine transcarbamylase-deficient mice. Molecular Therapy. 2006;14:1-2.  Abstract
  • Sun, B; Zhang, H; Benjamin, DK; 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. Molecular Therapy. 2006;14:822-830.  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. Molecular Therapy. 2005;12:876-884.  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. Molecular Therapy. 2005;11:889-898.  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. Molecular Therapy. 2005;11:57-65.  Abstract
  • Koeberl, DD; Young, SP; Gregersen, NS; Vockley, J; Smith, WE; Benjamin, DK; 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. Pediatric Research. 2003;54:219-223.  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. Molecular Therapy. 2003;7:467-477.  Abstract
  • Sun, BD; Chen, YT; Bird, A; Amalfitano, A; Koeberl, DD. Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV vector. Molecular Therapy. 2003;7:193-201.  Abstract
  • Beaty, RM; Jackson, M; Peterson, D; Bird, A; Brown, T; Benjamin, DK; 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 Therapy. 2002;9:1015-1022.  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;107:1184-1187.  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. Human Gene Therapy. 1999;10:2133-2140.  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. Proceedings of the National Academy of Sciences of USA. 1997;94:1426-1431.  Abstract
  • Koeberl, DD; McGillivray, B; Sybert, VP. Prenatal diagnosis of 45,X/46,XX mosaicism and 45,X: implications for postnatal outcome. The American Journal of Human Genetics. 1995;57:661-666.  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. The American Journal of Human Genetics. 1990;47:202-217.  Abstract
  • Bottema, CD; Koeberl, DD; Sommer, SS. Direct carrier testing in 14 families with haemophilia B. The Lancet. 1989;2:526-529.  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. The American Journal of Human Genetics. 1989;45:448-457.  Abstract
  • Stoflet, ES; Koeberl, DD; Sarkar, G; Sommer, SS. Genomic amplification with transcript sequencing. Science. 1988;239:491-494.  Abstract