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Dwight D. Koeberl, MD, PhD

Professor of Pediatrics
Professor in Molecular Genetics and Microbiology
Campus mail: 595 Lasalle Street, Gsrbi, Room 4006, Durham, NC 27710
Phone: (919) 681-9919
Email address: koebe001@mc.duke.edu

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.

Education and Training

  • Fellowship, Medical Genetics, University of Washington, 1992 - 1999
  • Resident, Pediatrics, University of California, San Francisco, School of Medicine, 1990 - 1992
  • Ph.D., Mayo School of Health Sciences, 1990
  • M.D., Mayo School of Health Sciences, 1990

Selected Grants and Awards

Publications

Han, Sang-Oh, Songtao Li, Angela McCall, Benjamin Arnson, Jeffrey I. Everitt, Haoyue Zhang, Sarah P. Young, Mai K. ElMallah, and Dwight D. Koeberl. “Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease.” Mol Ther Methods Clin Dev 17 (June 12, 2020): 133–42. https://doi.org/10.1016/j.omtm.2019.11.020.

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Han, Sang-Oh, Alexina C. Haynes, Songtao Li, Dennis M. Abraham, Priya S. Kishnani, Richard Steet, and Dwight D. Koeberl. “Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with Pompe disease.” Mol Genet Metab 129, no. 2 (February 2020): 73–79. https://doi.org/10.1016/j.ymgme.2019.10.005.

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Koeberl, Dwight D., Laura E. Case, Ankit Desai, Edward C. Smith, Crista Walters, Sang-Oh Han, Beth L. Thurberg, Sarah P. Young, Deeksha Bali, and Priya S. Kishnani. “Improved muscle function in a phase I/II clinical trial of albuterol in Pompe disease.” Mol Genet Metab 129, no. 2 (February 2020): 67–72. https://doi.org/10.1016/j.ymgme.2019.12.008.

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Yavarow, Zollie A., Hye-Ri Kang, Lauren R. Waskowicz, Boon-Huat Bay, Sarah P. Young, Paul M. Yen, and Dwight D. Koeberl. “Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia.” Hum Mol Genet 29, no. 2 (January 15, 2020): 286–94. https://doi.org/10.1093/hmg/ddz290.

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Farah, Benjamin L., Paul M. Yen, and Dwight D. Koeberl. “Links between autophagy and disorders of glycogen metabolism - Perspectives on pathogenesis and possible treatments.” Mol Genet Metab 129, no. 1 (January 2020): 3–12. https://doi.org/10.1016/j.ymgme.2019.11.005.

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Kang, Hye-Ri, Monika Gjorgjieva, Stephanie N. Smith, Elizabeth D. Brooks, Zelin Chen, Shawn M. Burgess, Randy J. Chandler, et al. “Pathogenesis of Hepatic Tumors following Gene Therapy in Murine and Canine Models of Glycogen Storage Disease.” Mol Ther Methods Clin Dev 15 (December 13, 2019): 383–91. https://doi.org/10.1016/j.omtm.2019.10.016.

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Kishnani, Priya S., Baodong Sun, and Dwight D. Koeberl. “Gene therapy for glycogen storage diseases.” Hum Mol Genet 28, no. R1 (October 1, 2019): R31–41. https://doi.org/10.1093/hmg/ddz133.

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Zhou, Jin, Lauren R. Waskowicz, Andrea Lim, Xiao-Hui Liao, Brian Lian, Hiroko Masamune, Samuel Refetoff, Brian Tran, Dwight D. Koeberl, and Paul M. Yen. “A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis in Glycogen Storage Disease Type Ia.” Thyroid 29, no. 8 (August 2019): 1158–67. https://doi.org/10.1089/thy.2019.0007.

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Bond, J. E., P. S. Kishnani, and D. D. Koeberl. “Immunomodulatory, liver depot gene therapy for Pompe disease.” Cell Immunol 342 (August 2019): 103737. https://doi.org/10.1016/j.cellimm.2017.12.011.

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Kishnani, Priya S., and Dwight D. Koeberl. “Liver depot gene therapy for Pompe disease.” Ann Transl Med 7, no. 13 (July 2019): 288. https://doi.org/10.21037/atm.2019.05.02.

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