Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• N-Acetylaspartate (NAA) is abundant in the brain, but its function is unclear.
• Canavan disease, a fatal neurometabolic disorder, results from aspartoacylase deficiency, leading to NAA accumulation and neurological decline.
• Current gene replacement therapies for Canavan disease have yielded suboptimal clinical outcomes.

Purpose of the Study:

• To identify the optimal cell type and target for gene replacement therapy in Canavan disease.
• To elucidate the cell-specific roles of NAA in neurological function and disease pathology.

Main Methods:

• Comprehensive phenotyping of novel mouse models with cell type-specific NAA manipulation (depletion or elevation).
• Conditional knockout of aspartoacylase in oligodendrocytes.
• Adeno-associated virus (AAV)-mediated gene replacement therapy targeting oligodendrocytes in Canavan disease mice.

Main Results:

• NAA deficiency impairs unconscious defensive reactions, suggesting NAA synthesis should not be eliminated.
• Elevated NAA levels in neurons did not cause neurological deficits, indicating NAA is not inherently neurotoxic.
• Eliminating aspartoacylase in oligodendrocytes recapitulated Canavan disease pathology; peripheral aspartoacylase mitigated CNS effects.
• Oligodendroglial gene replacement therapy reversed existing pathology and provided lasting neurological benefits in Canavan disease mice.

Conclusions:

• Optimal Canavan disease gene therapy should focus on restoring aspartoacylase in oligodendrocytes.
• Targeting oligodendrocytes with AAV-mediated gene therapy offers a promising therapeutic strategy for white matter disorders like Canavan disease.
• This study demonstrates the first successful post-symptomatic treatment of a white matter disorder via oligodendrocyte-targeted gene therapy.