A5024450225- Lysosomal Storage Disorders Research
- Virus-based gene therapy research
- RNA regulation and disease
- Cytomegalovirus and herpesvirus research
- Cellular transport and secretion
- Advanced Neuroimaging Techniques and Applications
- Glycosylation and Glycoproteins Research
- Neurological diseases and metabolism
- Trypanosoma species research and implications
- Neurogenetic and Muscular Disorders Research
- RNA Interference and Gene Delivery
- CRISPR and Genetic Engineering
- Autism Spectrum Disorder Research
- Retinal Development and Disorders
- Cerebral Palsy and Movement Disorders
- Fetal and Pediatric Neurological Disorders
- Herpesvirus Infections and Treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Spinal Dysraphism and Malformations
- Cancer-related molecular mechanisms research
- Adenosine and Purinergic Signaling
- Infectious Encephalopathies and Encephalitis
- Cardiovascular Conditions and Treatments
- Infant Nutrition and Health
- Calcium signaling and nucleotide metabolism
Nationwide Children's Hospital
2021-2024
University of California, Davis
2024
The Ohio State University
2022-2024
Office of Infectious Diseases
2024
University of Pennsylvania
2015-2023
Auburn University
2009-2023
The Ohio State University Wexner Medical Center
2022-2023
National Heart Lung and Blood Institute
2016
National Institutes of Health
2016
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2016
Krabbe disease is a lysosomal storage caused by mutations in the gene that encodes galactosylceramidase, which galactosylsphingosine (psychosine) accumulation drives demyelination central and peripheral nervous systems, ultimately progressing to death early childhood. Gene therapy, alone or combination with transplant, has been developed for almost two decades mouse models, increasing therapeutic benefit paralleling improvement of next-generation adeno-associated virus (AAV) vectors. This...
Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage caused by deficiency β-N-acetylhexosaminidase (Hex). While untreated mice reach humane endpoint 4.1 months age, treated single intracranial injection vectors expressing human hexosaminidase may live normal life span 2 years. When with same therapeutic used mice, two cats SD lived 7.0 and 8.2 compared an 4.5 ± 0.5 (n = 11)....
GM2 gangliosidoses, including Tay-Sachs disease and Sandhoff disease, are lysosomal storage disorders caused by deficiencies in β-N-acetylhexosaminidase (Hex). Patients afflicted primarily with progressive central nervous system (CNS) dysfunction. Studies mice, cats, sheep have indicated safety widespread distribution of Hex the CNS after intracranial vector infusion AAVrh8 vectors encoding species-specific α- or β-subunits at a 1:1 ratio. Here, study was conducted cynomolgus macaques (cm),...
Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, only experimental model that has clinical signs disease. The natural history sheep was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy tested AAVrh8 monocistronic vectors encoding α-subunit Hex (TSD α) or...
Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase. Most commonly, deficits galactosylceramidase result in widespread central and peripheral nervous system demyelination death affected infants typically by 2 years age. Hematopoietic stem-cell transplantation the current standard care children diagnosed prior to symptom onset. However, disease correction incomplete. Herein, first...
Sandhoff disease (SD) is an autosomal recessive neurodegenerative caused by a mutation in the gene for β-subunit of β-N-acetylhexosaminidase (Hex), resulting inability to catabolize ganglioside GM2 within lysosomes. SD presents with accumulation and its asialo derivative GA2, primarily central nervous system. Myelin-enriched glycolipids, cerebrosides sulfatides, are also decreased corresponding dysmyelination. At present, no treatment exists SD. Previous studies have shown therapeutic...
Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem transplantation (HSCT) only treatment for infantile-onset GLD; however, clinical outcomes HSCT recipients often remain poor, procedure-related...
GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in mice and cats have prompted consideration human clinical trials, yet there remains paucity objective biomarkers to track status. We developed panel blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, magnetic resonance spectroscopy cats—either untreated or AAV treated for more than 5 years—and compared them...
Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy 2-hydroxypropyl-<i>β</i>-cyclodextrin (HP<i>β</i>CD) in animal models resulted initiation phase I/IIa clinical trial 2013 and IIb/III 2015. With trials ongoing, validation biomarker to track progression serve as supporting outcome measure has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations...
Feline models of neurologic diseases, such as lysosomal storage leukodystrophies, Parkinson's disease, stroke and NeuroAIDS, accurately recreate many aspects human disease allowing for comparative study neuropathology the testing novel therapeutics. Here we describe in vivo visualization fine structures within feline brain that were previously only visible post mortem.3Tesla MR images acquired using T1-weighted (T1w) 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence (0.4mm...
Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a debilitating and always fatal pediatric neurodegenerative disease caused by mutation in the gene encoding hydrolytic enzyme galactosylceramidase (GALC). In absence of GALC, progressive loss myelin accumulation neurotoxic substrate lead to incapacitating motor cognitive function death, typically 2 years age. Currently, there no cure. Recent convincing evidence therapeutic potential combining therapies murine model GLD has...