A5045419573- Lysosomal Storage Disorders Research
- Glycogen Storage Diseases and Myoclonus
- Genetics and Neurodevelopmental Disorders
- Biochemical and Molecular Research
- Metabolism and Genetic Disorders
- Virus-based gene therapy research
- Neurogenetic and Muscular Disorders Research
- Trypanosoma species research and implications
- Mitochondrial Function and Pathology
- Carbohydrate Chemistry and Synthesis
- Adenosine and Purinergic Signaling
- CRISPR and Genetic Engineering
- Folate and B Vitamins Research
- RNA regulation and disease
- Amino Acid Enzymes and Metabolism
- Neonatal Health and Biochemistry
- Genomics and Rare Diseases
- Cytomegalovirus and herpesvirus research
- Diet and metabolism studies
- Oral and gingival health research
- Calcium signaling and nucleotide metabolism
- Muscle metabolism and nutrition
- RNA modifications and cancer
- Pancreatic function and diabetes
- Hemophilia Treatment and Research
Duke University
2016-2025
Duke Medical Center
2015-2024
Duke University Hospital
2009-2024
Duke University Health System
2020-2024
Clinical Research Institute
2015
Institute of Biomedical Sciences, Academia Sinica
2009
Fred Hutch Cancer Center
1995-2000
Children's Medical Research Institute
1997
University of Washington Medical Center
1997
Mayo Clinic
1990
Abstract Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA PCCB) subunits that leads to an accumulation of toxic metabolites and recurrent, life-threatening metabolic decompensation events. Here we report interim analyses first-in-human, phase 1/2, open-label, dose-optimization study extension evaluating safety efficacy mRNA-3927, dual mRNA therapy encoding PCCA PCCB. As 31 May 2023, 16 participants were enrolled across 5 dose...
We previously found that gene transduction by adeno-associated virus (AAV) vectors in cell culture can be stimulated over 100-fold treatment of the target cells with agents affect DNA metabolism, such as irradiation or topoisomerase inhibitors. Here we show previous γ-irradiation increased rate mouse liver up to 900-fold, and inhibitor etoposide about 20-fold. Similar rates hepatic were obtained direct injection systemic delivery via tail vein injection. Hepatocytes much more efficiently...
Liver delivery of engineered GAA transgenes to mice with Pompe disease rescued glycogen accumulation in multiple tissues.
Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid α-glucosidase (GAA; maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, respiratory failure. Adeno-associated virus vectors containing either liver-specific promoter (LSP) (AAV-LSPhGAApA) or hybrid CB (AAV-CBhGAApA) to drive human GAA expression were pseudotyped AAV8 administered immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day 12 weeks...
Glycogen storage disease type II (GSD-II; Pompe disease) causes death in infancy from cardiorespiratory failure. The underlying deficiency of acid α-glucosidase (GAA; maltase) can be corrected by liver-targeted gene therapy GSD-II, if secretion GAA is accompanied receptor-mediated uptake cardiac and skeletal muscle. An adeno-associated virus (AAV) vector encoding human (h) was pseudotyped as AAV8 (AAV2/8) injected intravenously into immunodeficient GSD-II mice. High levels hGAA were...
Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette drive GAA expression (AAV-LSPhGAA) established in knockout (KO) mice, whereas ubiquitous AAV-CBhGAA provoked responses. Therefore, we investigated the hypothesis that induced by hepatic-restricted was dominant. AAV-LSPhGAA and were administered singly or combination...
Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of formation antibody responses. The present study compared efficacy ERT against gene transfer an adeno-associated viral (AAV) vector containing a liver-specific promoter. knockout (KO) mice were administered either weekly injection rhGAA (20 mg/kg) or single AAV2/8-LSPhGAA (8 × 1011...
Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement (ERT) by creating a liver depot acid α-glucosidase (GAA) production. We report initial safety and bioactivity of first dose (1.6 × 10
Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid α-glucosidase (GAA; maltase) deficiency. An AAV2 vector pseudotyped as AAV6 (AAV2/6 vector) transiently expressed high-level human GAA GAA-knockout (GAA-KO) mice without reducing glycogen storage; however, immunodeficient GAA-KO/SCID the AAV2/6 and reduced content of injected muscle for 24 weeks. A CD4+/CD8+ lymphocytic infiltrate was observed response immunocompetent GAA-KO...
Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) optimize tropism. Survival prolonged in 2-week-old (–/–) mice 600-fold fewer AAV2/8 vector particles (vp), comparison previous experiments involving this model (2 × 109 vp; 3 1011 vp/kg). When AAV1, survival only at higher dose (3 1013 The...
Infantile Pompe disease progresses to a lethal cardiomyopathy in absence of effective treatment. Enzyme-replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has been most patients disease, but efficacy was reduced by high-titer antibody responses. Immunomodulatory gene low dose adeno-associated virus (AAV) vector (2 × 1010 particles) containing liver-specific regulatory cassette significantly lowered immunoglobin G (IgG), IgG1, and IgE antibodies GAA mice, when...
Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential for hepcidin expression. Hepcidin is the key peptide hormone in iron homeostasis, secreted predominantly by hepatocytes. HJV expression detected hepatocytes, as well skeletal heart muscle. binds BMP6 increases presumably acting a BMP co-receptor. We characterized role of hepatocyte regulation In HJV-null (Hjv(-/-)) mice that have severe overload marked suppression expression, we 4-fold higher hepatic mRNA than...