High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy.

Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE-/- mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors.

Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart.

Gene therapy is a promising new treatment option for cardiac diseases. For finding the most suitable and safe vector for cardiac gene transfer, we delivered adenovirus (AdV), adeno-associated virus (AAV) and lentivirus (LeV) vectors into the mouse heart with sophisticated closed-chest echocardiography-guided intramyocardial injection method for comparing them with regards to transduction efficiency, myocardial damage, effects on the left ventricular function and electrocardiography (ECG). AdV had the highest transduction efficiency in cardiomyocytes followed by AAV2 and AAV9, and the lowest efficiency was seen with LeV. The local myocardial inflammation and fibrosis in the left ventricle (LV) was proportional to transduction efficiency. AdV caused LV dilatation and systolic dysfunction. Neither of the locally injected AAV serotypes impaired the LV systolic function, but AAV9 caused diastolic dysfunction to some extent. LeV did not affect the cardiac function. We also studied systemic delivery of AAV9, which led to transduction of cardiomyocytes throughout the myocardium. However, also diffuse fibrosis was present leading to significantly impaired LV systolic and diastolic function and pathological ECG changes. Compared with widely used AdV vector, AAV2, AAV9 and LeV were less effective in transducing cardiomyocytes but also less harmful. Local administration of AAV9 was safer and more efficient compared with systemic administration.

Lack of cardiac and high-fat diet induced metabolic phenotypes in two independent strains of Vegf-b knockout mice.

Vascular endothelial growth factor-B (VEGF-B) has been implicated to play a significant role in coronary vessel growth and endothelial uptake and transport of fatty acids in heart and skeletal muscle. Additionally, recent studies have shown that Vegf-b deficiency protects from high-fat diet (HFD)-induced diabetes and insulin resistance. We compared the cardiac function and the effects of HFD on body composition and glucose metabolism in two available Vegf-b knockout (Vegf-b(-/-) strains) mouse strains side by side with their respective littermate controls. We found no differences in HFD-induced weight gain, glucose tolerance or insulin resistance between the Vegf-b(-/-) strains and their littermate control mice. Furthermore, there was no difference in basal cardiac function and cardiac expression of genes involved in glucose or fatty acid metabolism between the Vegf-b(-/-) strains and their littermate control mice. We conclude that VEGF-B is dispensable for normal cardiac function under unstressed conditions and for HFD-induced metabolic changes.