A new report on phase 2 studies using antisense inhibitors gene therapy to improve serum cholesterol levels has found that the therapy significantly reduced levels of the modified LDL particle, lipoprotein a (Lpa).
Lp(a) is simply an LDL particle to which another protein called apoprotein (a) – that binds lipids to form lipoproteins – is attached. We can think of Lp(a) as a “special” kind of LDL particle that increases cardiovascular risk.
Elevated Lp(a) levels is considered especially a major genetic risk factor for atherosclerosis, a serious type 2 diabetes complication.
Lp(a) has been an underappreciated risk factor for many years, so physicians haven’t measured or monitored Lp(a) levels closely. Yet, research has shown it plays a role in the development of atherosclerosis, especially in insulin resistant individuals.
The progression from a completely normal artery to an atherosclerotic one (characterised by the formation of plaque following an inflammatory response) which may or may not be “clogged” can be worsened by the presence of elevated Lp(a).
Research has suggested that high Lp(a) may drive the atherosclerotic process by fostering fat build-up and retention on artery walls, and it may also elicit an even greater immune response.
The results of these two randomized, double-blind, placebo-controlled clinical trials, published in the journal Lancet, show that two antisense oligonucleotides, which can silence a gene’s effect by altering or reducing its expressio, may be used to get Lp(a) levels back to normal.
The two drugs identified by researchers, known as Ionis-APO(a)-Lrx and Ionis-APO(a)rx, appear to be able to reduce Lp(a) levels in patients by targeting the “factory” that makes Lp(a), the hepatocyte.
In the first trial, 64 participants randomized to receive 100 to 300 mg of Ionis-APO(a)rx once a week for four weeks experienced Lp(a) reductions ranging from 66.8 per cent, for those who had concentrations between 125 to 437 nmol/L, to 71.6 per cent for participants whose Lp(a) concentrations were over 438 nmol/L.
During the second phase of the experiment, the researchers evaluated Ionis-APO(a)-Lrx. They found that among 30 participants who received 10 to 40 mg of the drug for 36 days, those in the 10-mg group had a 66 per reduction in Lp(a), while those in the 40-mg group had a 92 per cent reduction in Lp(a).
The researchers also saw significant reductions in other risk markers for atherosclerosis, such as overall LDL cholesterol, apolipoprotein B, and oxidized lipids, in patients receiving both drugs.

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