Physicians

Departments / Divisions

• Pediatrics / Pediatrics-Medical Genetics
• Molecular Genetics and Microbiology

Address
DUMC 103856
Durham, NC 27710

Appointment Telephone
919-684-2036

Office Telephone
919-681-9919

Fax Telephone
919-684-0983

Training

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

Residency

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

Fellowship

• 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 new therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 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 and acid -glucosidase (GAA) in GSD type II (Pompe disease). G6Pase deficiency in GSD type Ia affects primarily liver and kidney, while GAA deficiency in GSD type II 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. AAV vectors transduced liver and striated muscle to replace the deficient enzyme in GSD type Ia and GSD type II mice, respectively. We subsequently demonstrated efficacy through reductions in glycogen storage and correction of associated biomarkers.
1) GSD type Ia: G6Pase-knockout mice provided a model for the biochemical abnormalities of GSD type Ia, although early mortality complicates research with both the murine and canine models of GSD type 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.
2) GSD type II/Pompe disease: Pompe disease is characterized by the massive accumulation of lysosomal glycogen in striated muscle with an accompanying disruption of cellular functions. 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.
3) PKU: We demonstrated long-term biochemical correction of PKU in mice with an AAV2 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.

Industry Relationships and Collaborations (What's this?)

This faculty member (or a member of their immediate family) has a working relationship (i.e. consulting, research, and/or educational services) with the companies listed below. These relations have been reported to the health system leadership and, when appropriate, management plans are in place to address potential conflicts.

• Amicus Therapeutics
• Genzyme Corporation (Sanofi Aventis)
• Gerson Lehrman Group, Inc.
• Synpac/SVC Services

Representative Publications
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. 2013;27:34-44. (2013) 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. (2012) Abstract

Koeberl, DD; Li, S; Dai, J; Thurberg, BL; Bali, D; Kishnani, PS. ß2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease. Molecular Genetics and Metabolism. 2012;105:221-227. (2012) 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. (2012) 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. (2011) 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. (2010) 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. (2009) 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. (2009) 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. Journal of Gene Medicine. 2009;11:913-920. (2009) 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. (2008) 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. (2008) 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. (2008) 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. (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. Molecular Therapy. 2007;15:1253-1258. (2007) 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. American Journal of Human Genetics. 2007;81:1042-1049. (2007) 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 (Basingstoke). 2006;13:457-462. (2006) Abstract

Koeberl, DD. Vector-related tumorigenesis not found in ornithine transcarbamylase-deficient mice. Molecular Therapy. 2006;14:1-2. (2006) 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. (2006) 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. (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. Molecular Therapy. 2005;11:889-898. (2005) 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. (2005) 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. (2003) 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. (2003) 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. (2003) 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 (Basingstoke). 2002;9:1015-1022. (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;107:1184-1187. (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. Human Gene Therapy. 1999;10:2133-2140. (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. Proceedings of the National Academy of Sciences of USA. 1997;94:1426-1431. (1997) Abstract

Koeberl, DD; McGillivray, B; Sybert, VP. Prenatal diagnosis of 45,X/46,XX mosaicism and 45,X: implications for postnatal outcome. American Journal of Human Genetics. 1995;57:661-666. (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. American Journal of Human Genetics. 1990;47:202-217. (1990) Abstract

Bottema, CD; Koeberl, DD; Sommer, SS. Direct carrier testing in 14 families with haemophilia B. Lancet. 1989;2:526-529. (1989) 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. American Journal of Human Genetics. 1989;45:448-457. (1989) Abstract

Stoflet, ES; Koeberl, DD; Sarkar, G; Sommer, SS. Genomic amplification with transcript sequencing. Science. 1988;239:491-494. (1988) Abstract