Antisense therapy holds promise for treatment-resistant dyslipidemia
MedWire News: Review findings suggest that patients with treatment-resistant dyslipidemia may benefit from antisense therapy with mipomersen, an antisense molecule capable of producing clinically meaningful reductions in low-density lipoprotein (LDL) cholesterol.
"Because a significant percentage of patients who require high-dose statin therapy for dyslipidemia experience treatment-related muscle symptoms and an inconsistent clinical response, alternative or adjunctive approaches to the management of dyslipidemia are needed," says study author Peter Toth (University of Illinois College of Medicine, Peoria, USA).
Indeed, research has shown that up to 60% of patients with familial hypercholesterolemia (FH) do not achieve the US Adult Treatment Panel III guidelines goal.
The antisense therapy investigated the most to date for lipid management is mipomersen, which has an oligonucleotide sequence that is complementary to the apolipoprotein B-100 (apoB-100) mRNA sequence and codes the protein necessary for very low-density lipoprotein. Since apoB is contained within each atherogenic particle in plasma, it represents a high-value therapeutic target for dyslipidemia.
This technology allows control of gene expression at the translational level without the need for metabolism by the CYP450 system. It therefore possesses an important advantage for FH patients who typically receive multidrug therapy.
In the review, Toth outlined the methodological challenges encountered with antisense oligonucleotide (ASO) therapy, stating that the technology has undergone a series of enhancements for molecular stability, potency, and tolerability.
Unmodified ASOs are rapidly degraded and approaches to enhance their stability have been key to developing an effective delivery system. Indeed, ASOs have undergone structural modifications through three generations, overcoming cellular toxicity, poor affinity, nuclease resistance, and specificity.
Mipomersen, a second generation ASO, has yielded promising results in clinical trials showing significant LDL cholesterol reductions of 21-34% in patients with homozygous FH.
However, a number studies revealed elevated transaminases in approximately 12% of patients. Injection site reactions were the most common adverse event, although Toth calls for careful long-term monitoring of patients for immune reactions.
"ASO therapy targeting apoB synthesis appears to be a promising adjunctive treatment for refractory dyslipidemia in patients with FH who have not responded adequately or are intolerant to statins or conventional therapy," concludes Toth in the Journal of Clinical Lipidology.
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By Ingrid Grasmo