Metabolic correction in microglia derived from Sandhoff disease model mice

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Sandhoff disease is a lysosomal storage disorder linked to HEXB gene defects.
• Microglial activation plays a role in the neuroinflammation and neurodegeneration seen in Sandhoff disease.
• Accumulation of GM2 gangliosides and N-acetylglucosamine-terminated oligosaccharides characterizes the disease.

Purpose of the Study:

• To investigate the therapeutic potential of gene therapy for microglial cells in Sandhoff disease.
• To assess the efficacy of a lentiviral vector encoding the murine Hex beta-subunit for metabolic correction.
• To evaluate the uptake and degradation of accumulated substrates by recombinant human HexA isozyme in Sandhoff disease microglia.

Main Methods:

• Primary microglial cells were isolated from Sandhoff disease model mice (SD mice).
• A lentiviral vector encoding the murine Hex beta-subunit was used to transduce SD microglia.
• Recombinant human HexA isozyme was administered to SD microglia to assess substrate degradation via specific receptors.

Main Results:

• Transduction of SD microglia with the lentiviral vector reduced intracellular GM2 and oligosaccharide accumulation.
• Transduced cells secreted Hex isozyme activities.
• Recombinant HexA was incorporated into SD microglia and degraded accumulated substrates.

Conclusions:

• Gene therapy with a lentiviral vector encoding the Hex beta-subunit shows therapeutic potential for Sandhoff disease microglia.
• Recombinant human HexA isozyme can be taken up by microglia and correct the metabolic defect.
• These approaches offer promising strategies for metabolic cross-correction in Sandhoff disease-affected microglial cells.