Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector

Area of Science:

• Biochemistry
• Genetics
• Gene Therapy

Background:

• Methylmalonic aciduria is a rare metabolic disorder with severe consequences and limited treatment options.
• Organ transplantation shows promise, but gene therapy presents a more accessible therapeutic avenue.

Purpose of the Study:

• To evaluate the efficacy of lentiviral vector-mediated gene transfer for treating methylmalonic aciduria in a mouse model.

Main Methods:

• A lentiviral vector expressing a human methylmalonyl coenzyme A mutase transgene was administered intravenously to a mouse model of methylmalonic aciduria (Mut(-/-)MUT(h2)).
• Biochemical markers, including plasma and hepatic methylmalonic acid levels, and enzyme expression were assessed.

Main Results:

• Treated mice showed near-normal weight gain and significant expression of methylmalonyl coenzyme A mutase in the liver.
• Normalization of liver enzyme activity correlated with reduced plasma and urine methylmalonic acid levels.

Conclusions:

• Lentiviral vector gene therapy achieved significant biochemical correction of methylmalonic aciduria in mice.
• This study suggests gene therapy is a viable potential treatment for methylmalonic aciduria.