Related Experiment Video
Updated: Nov 1, 2025
Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 to Treat Neuromuscular Diseases in Rodents
Published on: August 10, 2018
Central nervous system-targeted adeno-associated virus gene therapy in methylmalonic acidemia
Francis J May1,2,3, PamelaSara E Head1, Leah E Venturoni1
1Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
Abstract:
Methylmalonic acidemia (MMA) is a severe metabolic disorder most commonly caused by a mutation in the methylmalonyl-CoA mutase (MMUT) gene. Patients with MMA experience multisystemic disease manifestations and remain at risk for neurological disease progression, even after liver transplantation. Therefore, delivery of MMUT to the central nervous system (CNS) may provide patients with neuroprotection and, perhaps, therapeutic benefits. To specifically target the brain, we developed a neurotropic PHP.eB vector that used a CaMKII neuro-specific promoter to restrict the expression of the MMUT transgene in the neuraxis and delivered the adeno-associated virus (AAV) to mice with MMA. The PHP.eB vector transduced cells in multiple brain regions, including the striatum, and enabled high levels of expression of MMUT in the basal ganglia. Following the CNS-specific correction of MMUT expression, disease-related metabolites methylmalonic acid and 2-methylcitrate were significantly (p < 0.02) decreased in serum of treated MMA mice. Our results show that targeting MMUT expression to the CNS using a neurotropic capsid can decrease the circulating metabolite load in MMA and further highlight the benefit of extrahepatic correction for disorders of organic acid metabolism.
Insights
Methylmalonic acidemia (MMA) is a severe metabolic disorder. Gene therapy targeting the central nervous system (CNS) with a neurotropic vector successfully reduced disease metabolites in MMA mice, offering potential neuroprotection.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Metabolic Disorders
Background:
- Methylmalonic acidemia (MMA) is a severe inherited metabolic disorder caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene.
- Patients with MMA face multisystemic complications and neurological disease progression, even post-liver transplant.
Purpose of the Study:
- To investigate the potential of delivering the MMUT gene to the central nervous system (CNS) for neuroprotection in MMA.
- To develop and test a neurotropic adeno-associated virus (AAV) vector for targeted MMUT expression in the brain.
Main Methods:
- Development of a neurotropic PHP.eB vector with a CaMKII promoter for CNS-specific MMUT expression.
- Administration of the AAV-PHP.eB vector to MMA mice.
- Analysis of MMUT expression, metabolite levels (methylmalonic acid, 2-methylcitrate), and transduction in brain regions.
Main Results:
- The PHP.eB vector successfully transduced cells in multiple brain regions, including the striatum.
- High levels of MMUT expression were achieved in the basal ganglia following CNS-specific correction.
- Significant reduction (p < 0.02) in serum levels of methylmalonic acid and 2-methylcitrate in treated MMA mice.
Conclusions:
- Targeting MMUT expression to the CNS via a neurotropic vector effectively decreased circulating disease metabolites in MMA mice.
- This approach highlights the therapeutic benefits of extrahepatic correction for metabolic disorders like MMA.
- CNS-targeted gene therapy offers a promising strategy for neuroprotection in patients with MMA.
More Related Videos
08:11Methods and Tips for Intravenous Administration of Adeno-associated Virus to Rats and Evaluation of Central Nervous System Transduction
Published on: August 25, 2017
05:03Author Spotlight: Developing Gene Therapies for Muscular Dystrophies and Neuromuscular Disorders
Published on: August 23, 2024
