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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

Publications

Han, SO, Ronzitti, G, Arnson, B, Leborgne, C, Li, S, Mingozzi, F, and Koeberl, D. "Erratum: Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction (Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction (2017) 4 (126–136), (S2329050117300049), (10.1016/j.omtm.2016.12.010))(Accepted)." Molecular Therapy Methods and Clinical Development 13 (June 14, 2019): 431-null.

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Kang, H-R, Waskowicz, L, Seifts, AM, Landau, DJ, Young, SP, and Koeberl, DD. "Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia.(Accepted)" Molecular Therapy. Methods & Clinical Development 13 (June 2019): 265-273.

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Han, S-O, Li, S, Everitt, JI, and Koeberl, DD. "Salmeterol with Liver Depot Gene Therapy Reversed Biochemical and Autophagic Abnormalities of Skeletal Muscle in Pompe Disease." 22nd Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT). Washington, DC. April 29, 2019 - May 2, 2019.: CELL PRESS, April 22, 2019.

Scholars@Duke

Han, S-O, Li, S, Everitt, JI, and Koeberl, DD. "Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease." Human Gene Therapy (April 5, 2019).

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Hannah, WB, Case, LE, Walters, C, Kishnani, PS, and Koeberl, DD. "SUMMARY OF SCREENING DATA FROM 19 PATIENTS WITH LATE-ONSET POMPE DISEASE FOR A PHASE I CLINICAL TRIAL OF AAV VECTOR-MEDIATED GENE THERAPY." 41st Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD). Bellevue, WA. April 6, 2019 - April 9, 2019.: ACADEMIC PRESS INC ELSEVIER SCIENCE, March 1, 2019.

Scholars@Duke

Han, S-O, Li, S, and Koeberl, DD. "Salmeterol with liver depot gene enhances the skeletal muscle response in murine Pompe disease.": Elsevier BV, February 2019.

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Waskowicz, LR, Zhou, J, Landau, DJ, Brooks, ED, Lim, A, Yavarow, ZA, Kudo, T, Zhang, H, Wu, Y, Grant, S, Young, SP, Huat, BB, Yen, PM, and Koeberl, DD. "Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia." Human Molecular Genetics 28, no. 1 (January 2019): 143-154.

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Brooks, ED, Kishnani, PS, and Koeberl, DD. "Letter to the Editors: Concerning "Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia" by Lee et al." Journal of Inherited Metabolic Disease 41, no. 6 (November 2018): 913-914. (Letter)

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Brooks, ED, Landau, DJ, Everitt, JI, Brown, TT, Grady, KM, Waskowicz, L, Bass, CR, D'Angelo, J, Asfaw, YG, Williams, K, Kishnani, PS, and Koeberl, DD. "Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy." November 2018.

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Koeberl, DD, Case, LE, Smith, EC, Walters, C, Han, S-O, Li, Y, Chen, W, Hornik, CP, Huffman, KM, Kraus, WE, Thurberg, BL, Corcoran, DL, Bali, D, Bursac, N, and Kishnani, PS. "Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease." Molecular Therapy : the Journal of the American Society of Gene Therapy 26, no. 9 (September 2018): 2304-2314.

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