AAV9-mediated gene therapy restores liver function in the MEGDHEL mouse model

Area of Science:

• Mitochondrial Biology
• Genetics
• Gene Therapy

Background:

• MEGDHEL syndrome is a severe mitochondrial disorder linked to SERAC1 gene mutations.
• Neonatal liver failure and high mortality are characteristic of MEGDHEL syndrome.
• Current treatments for MEGDHEL syndrome are lacking.

Purpose of the Study:

• To evaluate the efficacy of AAV9-SERAC1 gene therapy in a mouse model of MEGDHEL syndrome.
• To investigate the impact of gene therapy on liver dysfunction and mitochondrial impairments.

Main Methods:

• Utilized AAV9-SERAC1 gene therapy in Serac1-/- mice.
• Administered 4 x 10^11 viral genomes per mouse.
• Assessed liver histology, mitochondrial morphology and function via electron microscopy, respiratory complex activity, mtDNA content, and behavioral tests.

Main Results:

• Gene therapy improved liver histology, reducing fatty degeneration and cholesterol accumulation.
• Mitochondrial morphology and function were enhanced, with restored cristae and increased mitochondria.
• Respiratory complex activity and mtDNA content increased, alongside significant improvements in motor coordination and strength.

Conclusions:

• AAV9-SERAC1 gene therapy demonstrates potential in ameliorating liver dysfunction in MEGDHEL syndrome.
• The therapy improved mitochondrial function and locomotor abilities in the affected mouse model.
• This study presents a promising therapeutic strategy for MEGDHEL syndrome.