Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.
Shengwen ZhangAmy BastilleSusana GordoNikhil RameshJenisha VoraElizabeth McCarthyXiaohan ZhangDylan FrankChih-Wei KoCarmen WuNoel WalshShreya AmarwaniJing LiaoQiang XiongLauren DrouinMatthias HebbenKyle ChiangB Nelson ChauPublished in: PloS one (2022)
Methylmalonic acidemia (MMA) is an inborn error of metabolism mostly caused by mutations in the mitochondrial methylmalonyl-CoA mutase gene (MMUT). MMA patients suffer from frequent episodes of metabolic decompensation, which can be life threatening. To mimic both the dietary restrictions and metabolic decompensation seen in MMA patients, we developed a novel protein-controlled diet regimen in a Mmut deficient mouse model of MMA and demonstrated the therapeutic benefit of mLB-001, a nuclease-free, promoterless recombinant AAV GeneRideTM vector designed to insert the mouse Mmut into the endogenous albumin locus via homologous recombination. A single intravenous administration of mLB-001 to neonatal or adult MMA mice prevented body weight loss and mortality when challenged with a high protein diet. The edited hepatocytes expressed functional MMUT protein and expanded over time in the Mmut deficient mice, suggesting a selective growth advantage over the diseased cells. In mice with a humanized liver, treatment with a human homolog of mLB-001 resulted in site-specific genome editing and transgene expression in the transplanted human hepatocytes. Taken together, these findings support the development of hLB-001 that is currently in clinical trials in pediatric patients with severe forms of MMA.
Keyphrases
- genome editing
- crispr cas
- weight loss
- mouse model
- end stage renal disease
- endothelial cells
- ejection fraction
- clinical trial
- newly diagnosed
- healthcare
- public health
- physical activity
- dna damage
- stem cells
- prognostic factors
- poor prognosis
- oxidative stress
- small molecule
- genome wide
- bariatric surgery
- induced apoptosis
- dna repair
- cell death
- climate change
- protein protein
- cardiovascular disease
- risk assessment
- type diabetes
- high dose
- skeletal muscle
- copy number
- weight gain
- mesenchymal stem cells
- long non coding rna
- liver injury
- low dose
- adipose tissue
- coronary artery disease
- transcription factor
- endoplasmic reticulum stress
- fatty acid
- dna binding