Heart lipotoxicity gene therapy – LIPOCONTROL

The possible control of expression of genes involved in heart lipid overload proposes new strategies in pathophysiological situations like obesity and diabetes. We have shown that lipotoxicity (i.e. toxicity induced by lipids) and apoptosis/cell death can be reversed by the expression of smalln cardiac myoblasts. Because of the lack of safe drugs to lower lipotoxicity in patient’s organs, we plan first to test adeno-associated viruses (AAV) shRNA expression vectors to reduce in vivo target gene expression in the mouse heart, second to analyze the functional consequences, third to monitor the lipids levels and the changes in the heart lipotoxic and fibrotic status. This study will lead to novel applications to avoid heart lipotoxicity and failure.

We have first built then produced sufficient amount of non pathogenic adeno-associated vectors (AAV), and tested these vectors to modulate in vivo the target gene expression in the mouse heart by systemic a single injection of the AAV targeting this gene. Moreover, we have modified the expression of the transgene by adding cardiac specific regulatory sequences in the viral vector. We then analyzed by high resolution echocardiography the function consequences on the myocardium in high fat diet or normal chow fed mice. We further analyzed the heart lipotoxic and fibrotic status, lipids, enzymatic activities and heart gene expression levels.
Main results
After a single dose AAV injection targeting thie gene of interest, we were able to strongly reduce its mRNA and protein levels and to prevent from heart lipotoxicity. Therefore, the cardiac function of the mice was protected during the high fat diet. Since AAV are known to remain
upon a year in the human heart, we have validated the concept of a new strategy for long term cardioprotection in a lipotoxic situation as seen in diabetic or dyslipidemic patients.

This major results drives us to develop new molecules to modulate in vivo target genes for cardioprotection.

This work has led to a patent application with InsermTransfert. Moreover a publication is in preparation.

Obesity and diabetes are forerunners to secondary organ failure through excessive ectopic lipid deposition, leading to lipotoxicity. Lipotoxicity can be manifested as cardiomyopathy, myopathy, fatty liver, pancreatitis, retinopathy, hypothyroidism and diabetes. Heart lipotoxicity is considered as a first step towards the development of heart failure.
Through a functional genomics study aimed at identifying genes differentially regulated in the heart by obesity, we discovered a new apolipoprotein O (ApoO) as overexpressed in hearts from diabetic patients. We propose a model for the original molecular mechanisms accounting for ApoO features observed in vitro and in vivo in a mouse model overexpressing 2 fold physiological levels of human ApoO, as observed in human heart diseases. The involvement of ApoO in lipid metabolism reveals novel strategies to control lipid overload in pathophysiological situations like obesity, diabetes and cardiomyopathy. We plan to test adeno-associated vectors (AAVs) to modulate in vivo ApoO gene expression in the mouse heart and to monitor the functional consequences and second to analyze the lipids levels and the changes in the organs lipotoxic and fibrotic status.