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
- Genetic and Genomics Training Grant
- Viral Oncology Training Grant
- A Global, Phase 1/2, Open-label, Dose Escalation Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3927 in Participants with Propionic Acidemia
- Unified Program for Therapeutics in Children
- A Global, Phase 1/2, Open Label, Dose Escalation Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3704 in Patients with Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency
- A Phase 1 Study of the Safety of AAV8-LSPhGAA (ACTUS-101) in Late-onset Pompe Disease (LOPD)- Cohort II
- Genome editing for the correction of Pompe disease
- Reformulation of Pharmaceutical to Treat ALS
- Observational Study of Males with Creatine Transporter Deficiency
- Investigating Autophagy in GSD-Ia
- MaP: Mapping the Patient Journey in Methylmalonic and Propionic Acidemia
A longitudinal, exploratory, natural history study to further characterize and
describe the signs and symptoms of patients with organic acidemias - Identifying Pathogenic Non-Coding Mutations in Rare Mendelian Disease
- Feasibility of using Bortezomib-based immunosuppressive approach to deplete anti-AAV antibodies in mice
- A retrospective chart review study to assess the clinical outcome of triheptanoin treatment in patients with long-chain fatty acid oxidation disorders (LC-FAOD) treated under expanded access program
- Investigating Autophagy in GSD-Ia
- Genetics Training Grant
- Organization and Function of Cellular Structure
- Long Term Follow-up and Treatment Outcomes for Individuals with Pompe Disease
- Pharmacodynamic study using rhaGLU in a Pompe mouse model. Nonclinical GAA-KO mouse study design proposal rhaGLU
- A Phase I Study of the Safety of AAV2/8 LSPhGAA in Late-onset Pompe Disease
- Potency Assays
- Translational studies of GAA deficiency in bioengineered human muscle
- LDN: CRIM responses in Pompe disease
- Rapid Neonatal Testing for Ammonia Disorder Biomarkers
- Inborn Errors of Long Chain Fat Metabolism
- Activity and Biodistribution of the AAV2/8-LSPhGAA in GAA-knockout mice
- New Indications for Beta2 Agnoists in Glycogen Storage Disease Type Ia, NAFLD/NASH, and Pompe Disease
- TBR agonists for treatment in GSD Ia
- 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