HELPER-DEPENDENT ADENOVIRAL VECTORS FOR GENE THERAPY OF FAMILIAL HYPERCHOLESTEROLEMIA

Cardiovascular diseases (CD) are a major cause of mortality in western countries. One of the most important factor in the development of CD is hypercholesterolemia. Familial hypercholesterolemia (FH) is one of the most frequent genetic hyperlipidemias and it is caused by an alteration in the LDL receptor (LDLR). This alteration causes deposition of cholesterol in tendons, skin and arteries. Therapeutic options for FH patients are still poor and are extremely expensive and invasive.In our project we propose to evaluate an alternative therapy for FH on an animal model of the disease (LDLR-deficient mice) to acquire sufficient data for the application of this therapy on FH patients. At this aim, we plan to use genetically-modified viruses (adenoviral vectors) to express LDLR in the infected cells and correct the genetic defect in the above-mentioned mice; furthermore, our adenoviral vectors will allow expression of the apolipoprotein A-I, leading to an increase in HDL cholesterol (the so-called good cholesterol) with an additional reduction of cardiovascular risk. This therapeutic strategy would allow, with a single administration of adenoviral vectors, a long-lasting correction of the genetic defect and a reduction of cardiovascular risk, improving life expectancy and quality in FH patients. The described studies represents the basis for the transfer of this approach from research to clinical practice and to make this therapy accessible to patients.