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Updated: Nov 3, 2025
Mouse Models of Periventricular Leukomalacia
Published on: May 18, 2010
Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
Emilie Audouard1, Valentin Oger1, Béatrix Meha1
1NeuroGenCell, Institut du Cerveau et de la Moelle Épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France.
Abstract:
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.
Insights
Gene therapy using AAVPHP.eB-hARSA shows promise for metachromatic leukodystrophy (MLD). Intravenous delivery corrected sulfatide storage and reduced neuroinflammation in MLD mice, offering hope for progressive forms.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disorder caused by arylsulfatase A (ARSA) deficiency, leading to sulfatide accumulation and neurodegeneration.
- Current treatments are ineffective for the late infantile form of MLD after symptom onset, highlighting the urgent need for novel therapeutic strategies.
- Previous gene therapy attempts using AAVrh10 showed limited success in MLD patients, necessitating exploration of alternative delivery methods.
Purpose of the Study:
- To evaluate the efficacy of intravenous AAVPHP.eB-hARSA gene therapy in a mouse model of MLD with established pathology.
- To assess the impact of this gene therapy on sulfatide storage, astrogliosis, and microgliosis in the central nervous system.
Main Methods:
- A single intravenous injection of AAVPHP.eB-hARSA vector was administered to 6-month-old MLD mice exhibiting significant sulfatide accumulation.
- The expression of human ARSA cDNA was driven by the CAG promoter.
- Therapeutic effects were evaluated by measuring sulfatide levels and markers of neuroinflammation (astrogliosis and microgliosis) in the brain and spinal cord within 3 months post-injection.
Main Results:
- A single intravenous AAVPHP.eB-hARSA injection effectively corrected sulfatide storage in the brain and spinal cord of MLD mice.
- Treated animals showed significant improvement in astrogliosis and microgliosis, indicating a reduction in neuroinflammation.
- These short-term effects demonstrate the potential of this gene therapy approach in mitigating MLD pathology.
Conclusions:
- Intravenous AAVPHP.eB-hARSA gene therapy is a promising strategy for treating symptomatic, rapidly progressing forms of MLD.
- This approach warrants further investigation for clinical application in MLD patients.
- The study supports the consideration of AAVPHP.eB-hARSA for intravenous gene therapy in MLD.
