High-capacity adenoviral vector-mediated expression of an LDLR/transferrin chimeric protein in muscle reduces atherosclerosis in Ldlr-/- mice.

Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in the low-density lipoprotein (LDL) receptor, leading to impaired uptake of LDL and its accumulation in arterial walls and other tissues. This accumulation results in cardiovascular disease and early mortality. Treatments, including statins, ezetimibe, PCSK9 inhibitors, and bempedoic acid, are often insufficient in homozygous FH patients, particularly those with null mutations in the LDL receptor (LDLR). To address this unmet need, we have developed two helper-dependent adenoviral (HD-Ad) vectors for the expression of the murine and human versions of a protein composed of the extracellular portion of the LDLR fused to transferrin. In both cassettes, expression is driven by the murine creatine kinase promoter to obtain high levels of expression restricted to muscle cells, to mitigate host response to the fusion protein. Both human and murine proteins restored LDL uptake in Ldlrf-deficient cells, correcting the phenotype in vitro. A single intramuscular administration of the HD-Ad vector induced the expression of the murine fusion protein, leading to a 12-month improvement in the lipid profile, with a reduction in aortic atherosclerosis in Ldlr-deficient mice. Furthermore, we observed no major systemic toxicity, indicating that the present strategy may represent more effective therapy for FH patients.