Why the study?
Does intramuscular administration of a helper-dependent adenoviral vector expressing an LDLR/transferrin chimeric protein reduce atherosclerosis and improve lipid profiles in Ldlr-deficient mice?
Does intramuscular administration of a helper-dependent adenoviral vector expressing an LDLR/transferrin chimeric protein reduce atherosclerosis and improve lipid profiles in Ldlr-deficient mice?
Absolute Event Rate: 4.2% vs 17.4%
Intramuscular gene therapy expressing a secreted LDLR/transferrin chimeric protein effectively lowers LDL cholesterol and reduces aortic atherosclerosis in an FH mouse model without systemic toxicity, suggesting a viable therapeutic alternative for severe hypercholesterolemia.
Supports muscle-directed LDLR gene therapy in mouse models; leaves open translation to human familial hypercholesterolemia.
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.
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Vitale et al. (2026) studied Familial hypercholesterolemia (Ldlr-deficient mice) (n=10). HD-Ad-mLdlr/mTf vector vs. PBS was evaluated on Aortic atherosclerotic lesion area (% of total aortic surface).
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