Background: GM2 gangliosidosis is a neurodegenerative, lysosomal storage disease caused by the deficiency of β-hexosaminidase A enzyme (Hex A), an α/β-subunit heterodimer. A novel variant of the human hexosaminidase α-subunit, coded by HEX M, has previously been shown to form a stable homodimer, Hex M, that hydrolyzes GM2 gangliosides (GM2) in vivo.
Materials & Methods: The current study assessed the efficacy of intravenous (IV) delivery of a self-complementary adeno-associated virus serotype 9 (scAAV9) vector incorporating the HEXM transgene, scAAV9/HEXM, including the outcomes based on the dosages provided to the Sandhoff (SD) mice. Six-week-old SD mice were injected with either 2.5E+12 vector genomes (low dose, LD) or 1.0E+13 vg (high dose, HD). We hypothesized that when examining the dosage comparison for scAAV9/HEXM in adult SD mice, the HD group would have more beneficial outcomes than the LD cohort. Assessments included survival, behavioral outcomes, vector biodistribution, and enzyme activity within the central nervous system.
Results: Toxicity was observed in the HD cohort, with 8 of 14 mice dying within one month of the injection. As compared to untreated SD mice, which have typical survival of 16 weeks, the LD cohort and the remaining HD mice had a significant survival benefit with an average/median survival of 40.6/34.5 and 55.9/56.7 weeks, respectively. Significant behavioral, biochemical and molecular benefits were also observed. The second aim of the study was to investigate the effects of IV mannitol infusions on the biodistribution of the LD scAAV9/HEXM vector and the survival of the SD mice. Increases in both the biodistribution of the vector as well as the survival benefit (average/median of 41.6/49.3 weeks) were observed.
Conclusion: These results demonstrate the potential benefit and critical limitations of the treatment of GM2 gangliosidosis using IV delivered AAV vectors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.2174/1566523221666210916153051 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Clinical and biochemical abnormalities in a feline model of GM2 activator deficiency.
Mol Genet Metab
November 2024
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL 36849, United States of America; Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849, United States of America. Electronic address:
Though it has no catalytic activity toward GM2 ganglioside, the GM2 activator protein (GM2A) is essential for ganglioside hydrolysis by facilitating the action of lysosomal ß-N-acetylhexosaminidase. GM2A deficiency results in death in early childhood due to rapid central nervous system deterioration similar to the related GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease. This manuscript further characterizes a feline model of GM2A deficiency with a focus on clinical and biochemical parameters that may be useful as benchmarks for translational therapeutic research.
View Article and Find Full Text PDFA natural history study of pediatric patients with early onset of GM1 gangliosidosis, GM2 gangliosidoses, or gaucher disease type 2 (RETRIEVE).
Orphanet J Rare Dis
December 2024
Division of Metabolism and Children's Research Center, Reference Center for Inborn Errors of Metabolism, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland.
Background: The GM1 and GM2 gangliosidoses and type 2 Gaucher disease (GD2) are inherited lysosomal storage disorders with most cases having symptom onset in infancy and reduced life expectancy. The conditions are rare, and there is therefore a need for accurate and up to date information concerning the disease course and survival to assist in the design of clinical trials. RETRIEVE is a natural history study aiming to: (1) collect data on the survival of patients with early-onset (onset of first neurological manifestation before 24 months of age) GM1, GM2, or GD2; (2) collect data that could constitute a historical control group for future clinical trials; and (3) evaluate whether the conditions can be assessed together in a single interventional clinical trial.
View Article and Find Full Text PDFIntravenous gene therapy improves lifespan and clinical outcomes in feline Sandhoff Disease.
bioRxiv
November 2024
Scott Ritchey Research Center, Auburn University College of Veterinary Medicine; Auburn, AL, USA.
Sandhoff Disease (SD), a fatal neurodegenerative disorder, is caused by the absence of ß-hexosaminidase (Hex) and subsequent accumulation of GM2 ganglioside in lysosomes. Previous studies have led to adeno-associated virus (AAV) gene therapy for children with GM2 gangliosidosis in both expanded access and Phase I/II clinical trials via intracranial and/or cerebrospinal fluid-based delivery. The current study investigated intravenous (IV) gene therapy of SD cats, treated at one month of age with a bicistronic AAV vector.
View Article and Find Full Text PDFVoice of the Patient Report on GM2 Gangliosidosis (Tay-Sachs and Sandhoff).
Hum Gene Ther
November 2024
National Tay-Sachs & Allied Diseases Association (NTSAD), Boston, Massachusetts, USA.
4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model.
Hum Mol Genet
November 2024
Department of Biology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4K1, Canada.
Sandhoff disease (SD), a fatal and rare lysosomal storage disorder (LSD), is caused by a deficiency of the enzyme β-hexosaminidase B and leads to severe accumulation of GM2 gangliosides in lysosomes, primarily within the central nervous system (CNS). This accumulation results in severe neurological impairment, lower motor neuron disease, and death. Currently, there are no effective therapies available for SD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!