Dwight D. Koeberl, MD, PhD
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
- A Phase I Study of the Safety of AAV2/8 LSPhGAA in Late-onset Pompe Disease
- Genetics Training Grant
- Organization and Function of Cellular Structure
- Investigating Autophagy in GSD-Ia
- Observational Study of Males with Creatine Transporter Deficiency
- LDN: CRIM responses in Pompe disease
- Viral Oncology Training Grant
- Activity and Biodistribution of the AAV2/8-LSPhGAA in GAA-knockout mice
- Translational studies of GAA deficiency in bioengineered human muscle
- New Indications for Beta2 Agnoists in Glycogen Storage Disease Type Ia, NAFLD/NASH, and Pompe Disease
- TBR agonists for treatment in GSD Ia
- Inborn Errors of Long Chain Fat Metabolism
- Supplemental Funding for Phase 1/2 study of Clenbuterol for the Treatment of Pompe Disease
- Phase 1/2 Study of Clenbuterol for the Treatment of Pompe Disease
- Lysosomal enzymes, Glycosaminoglycans and Outflow Pathway Physiology
- Dietary therapy in mitochondrial trifunctional protein deficiency
- Training course for expanded (MS/MS) newborn screening laboratory follow-up coordinators
- Clinical Trial Planning in Pompe Disease
- Gene delivery to striated muscle by systemic AAV vectors
- Mechanisms for immune tolerance in Pompe Disease