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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

Bond, JE, Kishnani, PS, and Koeberl, DD. "Immunomodulatory, liver depot gene therapy for Pompe disease." Cellular immunology (December 29, 2017).

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Farah, BL, Landau, DJ, Wu, Y, Sinha, RA, Loh, A, Bay, B-H, Koeberl, DD, and Yen, PM. "Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia." Molecular genetics and metabolism 122, no. 3 (November 2017): 95-98.

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Puzzo, F, Colella, P, Biferi, MG, Bali, D, Paulk, NK, Vidal, P, Collaud, F, Simon-Sola, M, Charles, S, Hardet, R, Leborgne, C, Meliani, A, Cohen-Tannoudji, M, Astord, S, Gjata, B, Sellier, P, van Wittenberghe, L, Vignaud, A, Boisgerault, F, Barkats, M, Laforet, P, Kay, MA, Koeberl, DD, Ronzitti, G, and Mingozzi, F. "Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase." Science translational medicine 9, no. 418 (November 2017).

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Chien, Y-H, Hwu, W-L, Lee, N-C, Tsai, F-J, Koeberl, DD, Tsai, W-H, Chiu, P-C, and Chang, C-L. "Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease." Molecular genetics and metabolism reports 11 (June 2017): 31-35.

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Farah, BL, Sinha, RA, Wu, Y, Singh, BK, Lim, A, Hirayama, M, Landau, DJ, Bay, BH, Koeberl, DD, and Yen, PM. "Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)." Scientific reports 7 (March 20, 2017): 44408-.

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Han, S-O, Ronzitti, G, Arnson, B, Leborgne, C, Li, S, Mingozzi, F, and Koeberl, D. "Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction." Molecular Therapy - Methods & Clinical Development 4 (March 2017): 126-136.

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Bentler, K, Zhai, S, Elsbecker, SA, Arnold, GL, Burton, BK, Vockley, J, Cameron, CA, Hiner, SJ, Edick, MJ, Berry, SA, and Inborn Errors of Metabolism Collaborative, . "221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative." Molecular genetics and metabolism 119, no. 1-2 (September 2016): 75-82.

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Kansagra, S, Austin, S, DeArmey, S, Koeberl, D, and Kishnani, PS. "Death from supine asphyxia in late onset pompe disease: Two patients." American journal of medical genetics. Part A 170, no. 7 (July 2016): 1928-1929. (Letter)

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Koeberl, DD. "Vision of correction for classic homocystinuria." Journal of Clinical Investigation 126, no. 6 (June 2016): 2043-2044.

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Landau, DJ, Brooks, ED, Perez-Pinera, PP, Amarasekara, H, Mefferd, A, Li, S, Bird, A, Gersbach, CA, and Koeberl, DD. "311. In Vivo Zinc Finger Nuclease-Mediated Targeted Integration of a Glucose-6-Phosphatase Transgene Enhances Biochemical Correction in Mice with Glycogen Storage Disease Type IA." May 2016.

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