Exploiting regulatory T-cell metabolic reprogramming and vascular tropism as therapeutic tools for Familial Hypercholesterolaemia.

Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening disease (1 in 160.000 subjects) characterized clinically by plasma cholesterol levels >500 mg/dL, extensive xanthomas, and marked premature and progressive atherosclerotic cardiovascular disease. In heterozygosity familial hypercholesterolaemia (HeFH) has a frequency of 1 in 150 subjects. Studies in cultured fibroblasts from HoFH and HeFH patients showed a severe defect in the ability to bind and internalize LDL particles, subsequently shown to be caused by mutations in the alleles of the gene encoding the LDL receptor (LDLR). Recent genetic insights indicate that mutations in alleles of other genes, including APOB, PCSK9, and LDLRAP1 could also have a role. Untreated, most HoFH patients with markedly elevated LDL-C levels develop overt atherosclerosis before the age of 20 years, and generally do not survive past 30 years, while HeFH might have a severe cardiovascular event at the age of 35 years. As, HoFH is typically diagnosed when considerable coronary atherosclerosis has already developed and the diagnosis of HeFH occurs even later in life, the efficacy of LDL-apheresis and/or lipid lowering therapies, on controlling the burden of immunoinflammatory activation is limited. Novel therapeutic approaches, such as anti-PCSK9 monoclonal antibodies, are also poorly effective in HoFH patients, due to their mechanism of action, which consists in increasing LDL-R expression which however is not or poorly functional in FH patients. While current therapies aim at reducing the burden of elevated LDL-C levels, our proposal builds up on several experimental studies showing the presence of a robust immunoinflammatory response in the atherosclerotic plaque, often associated to decreased Treg activity. To date the translation of these aspects in experimental models and in patients with atherosclerotic diseases has been limited by the poor homing selectivity of the administered Treg and has not been explored in FH. This proposal aims at testing the potential of exploiting regulatory T-cell vascular tropism and immunometabolic reprogramming as a therapeutic tool for reducing the burden of plaque immunoinflammation in Familial Hypercholesterolaemia.