Speaker at Global conference on Pharmaceutics and Drug Delivery Systems 2019 - Nathalie Janel
Universite Paris Diderot, France
Title : Targeting liver function to circumvent neuronal and cardiac dysfunctions linked to hyperhomocysteinemia


Hyperhomocysteinemia is well recognized as an independent risk factor for cardiovascular diseases and is associated with diverse dysfunction. It’s the second most common amino acid metabolic disorder. If it is not treated, the life expectancy of these patients is greatly reduced, and cardiovascular events are the leading cause of death. However, all patients suffering from severe hyperhomocysteinemia do not respond favorably to drug treatments currently given. In order to protect the cardiovascular system from hyperhomocysteinemia, new substances with protective properties on both the vascular system and the cardiac system are sought. Our research program meets this need and find its originality by an innovative approach to biotherapy which could be considered a definitive and curative treatment, unlike a pharmacological approach. Plasma homocysteine level is an important reflection of hepatic methionine metabolism and the rate of processes modified by B vitamins as well as different enzyme activity. Reduction of homocysteine levels is the key objective in treatment of hyperhomocysteinemia. The liver is a central organ of metabolism and many metabolic diseases have their origin in the liver, although the clinical manifestations are extrahepatic. We recently found a negative correlation between plasma homocysteine level and the hepatic expression of an anti-inflammatory protein, Dyrk1A. Many studies indicated that overexpression of Dyrk1A, a serine/thronine kinase involved in diverse functions ranging from development and growth to apoptosis, not only causes developmental defects with life-long structural and functional consequences, but also contributes to neurodegeneration, neuronal death and loss of function observed in multiple neurodegenerative diseases. The proof of concept has already been obtained in mice by the use of an adenovirus adapted to murine model. It is now necessary to transfer technology to a vector applicable in humans that also will serve for preclinical studies. To do this, we decided to use a gene transfer strategy with a specific hepatic adeno-associated viral (AAV) serotype 8 vector expressing Dyrk1A to analyze the effect of this selective homocysteine lowering therapy upon molecular mechanisms linked to Dyrk1A overexpression in brain and heart of hyperhomocysteinemic mice. We conclude that specific hepatic Dyrk1A gene transfer restores the molecular mechanisms altered in brain and heart of hyperhomocysteinemic mice. The positive effect on plasma homocysteine and brain and heart signaling pathways demonstrates that this gene therapy can constitute a useful approach for prevention of cardiovascular diseases and neurodegenerative processes linked to hyperhomocysteinemia.


Nathalie Janel is professor at the university Paris Diderot in the research unit of functional and adaptive biology. She is currently director of the bachelor’s degree in Biology. She has a long-standing interest in the study of biochemical and physiological consequences of genetic alterations which lead to functional alterations affecting liver, vessels and brain. Her group is focusing on studying dysregulated signaling pathways in metabolic and cognitive diseases and develops a translational research to establish blood biomarkers. She is currently working on finding therapeutical strategies with viral vectors in order to specifically modulate these dysregulated pathways at the cellulal level. She has published more than 80 research articles in SCI(E) journals.