Human Heme Oxygenase Gene Therapy as a Treatment for Obesity-mediated Cardiovascular Disease

Obesity and concomitant cardiovascular disease and metabolic disorder have rapidly become a major threat to global health. The Farmington heart study (2006) found that primary hypertension is predominantly due to being overweight. Heme oxygenase-1 (HO-1) is highly expressed in Gilbert’s Syndrome patients and is associated with increased levels of serum of bilirubin (2-3 mg/dL), resulting in a reduction of cardiovascular disease.

HO is considered a promising therapeutic agent for Type 2 Diabetes/obesity. Previous studies have shown lentiviral-mediated delivery of human HO-1 mice sustained expression for 9 months as assessed by elevation of bilirubin. Native HO levels in obese subjects are highly reduced, making gene therapy an attractive strategy to achieve sustained circulating bilirubin levels.

In this study, lentiviral-adipo-human HO-1 was used to selectively modify inflamed fat cells to Brown-like fat cells. Treatment of C57 Mice under a long term high fat diet (60% fat), resulted in marked reduction of body weight, adipose tissue hypertrophy, insulin resistance (p<0.05), improved hepatic steatosis for 3 months. Expression of mitochondrial and thermogenic genes in heart tissue was normalized in obese mice treated with human HO-1 compared to untreated obese mice (p<0.05). ECHO data showed that left ventricular function (ejection fraction) improved by 60% in obese mice treated with HO lentivirus compared to untreated obese mice (35%, p<0.05).

This therapeutic effect was achieved without causing harmful side effects despite continuous elevated serum bilirubin levels up to 2-3mg/dL. Our study emphasizes the potential of HO gene therapy to treat obesity-mediated heart failure.