Mol Ther. 2026 Feb 13:S1525-0016(26)00100-0. doi: 10.1016/j.ymthe.2026.02.014. Online ahead of print.
ABSTRACT
Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor, leading to impaired uptake of low-density lipoprotein and its accumulation in arterial walls and other tissues. This accumulation results in cardiovascular disease and early mortality. Treatments, including statins, ezetimibe, and PCSK9 inhibitors, and bempedoic acid, are often insufficient in homozygous FH patients, particularly those with null mutations in the LDL receptor. To address this unmet need, we have developed two helper-dependent adenoviral 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 LDLR-deficient cells, correcting the phenotype in vitro. A single intramuscular administration of the HD-Ad vector induced expression of the murine fusion protein led to a twelve-month improving the lipid profile with a reduction of aortic atherosclerosis in LDLR-deficient mice. Furthermore, we observe no major systemic toxicity indicating that the present strategy may represent more effective therapy for FH patients.
PMID:41691368 | DOI:10.1016/j.ymthe.2026.02.014