By David Warmflash
Our society, and to some extent even clinical medicine, is focused on blood lipoproteins, especially low density lipoprotein (LDL, the “bad” cholesterol). LDL is at center stage for assessment of one’s risk, and also as a blood value to modify with drugs, such as statins, and dietary change. There are good reasons for this, but another serum value, triglycerides, also plays a key role, yet how many people are aware of their “trig” level?
Certainly, not as many could tell you their total and LDL cholesterol levels. But, especially in certain situations, serum triglycerides matter. Values 150–199 mg/dL (1.8 to 2.2 mmol/L) are borderline—a hint to keep an eye on trigs and to consider whether a patient might be consuming high levels of sugar and alcohol—but not a reason to worry. 200–499 mg/dL is high and brings triglycerides to center stage in women, and in men who have no other cardiovascular risk factors. 500 mg/dL and up warrants immediate attention, which could mean considering a triglyceride-lowering drug, including a new class that looks very promising. Along with risk for cardiovascular events, an elevated triglyceride value also entails a high risk for pancreatitis.
The target of new drugs is APOCIII, a protein receptor present on the outside of lipoproteins, including chylomicrons and very low-density lipoproteins (VLDL). These two types of lipoproteins transport triglycerides, and since the early 2000s scientists have known that deficiency of APOCIII, or the gene that encodes it (APOC3), accelerates removal of triglycerides, as shown in mouse models. Over the years, evidence has grown suggesting that the APOC3 gene is similarly important in humans. A few years ago, researchers realized that lack of the gene substantially reduced triglyceride levels in people, making APOC3 a logical target for blocking in people with a condition called Familial Chylomicronemia Syndrome (FCS), characterized by very high triglyceride levels.
Then, this year came a fascinating genome-wide in the journal Nature, revealing a fishing village in Pakistan. Due to interbreeding of first cousins, many people in that village lack both copies of the APOC3 gene that humans usually have. As a result, not only are their triglyceride levels low, but you can feed them milkshakes and the levels do not rise substantially, as they would in a normal individual.
Along with putting people at risk by way of making triglyceride levels high, the mere presence of the APOCIII receptor on lipoproteins may put people at risk for cardiovascular events, even when their triglyceride levels are not especially high. Since the presence of the one gene, APOC3, has so much of an effect, the prospect of CRISPR gene therapy should be attractive. One could try to knockout APOC3, but that will be science fiction for several years.
Meanwhile, some new drugs are working their way through basic research and clinical trials, trying to do effectively what CRISPR knockout would do. With an approach called antisense therapy, you can turn off the gene. An active gene, including APOC3, produces its gene product through a series of steps. The initial step is synthesis of a messenger RNA (mRNA) strand. Through Watson-Crick base pairing, the drug, in the form a complimentary strand, neutralizes the mRNA. This prevents the remaining steps that normally result in translation from gene sequence into the protein. Variations of the antisense strategy also can involve interfering with other steps in the process of protein synthesis. For instance, sections of mRNA strands can be targeted to prevent splicing out of introns that normally separate exons, the sections of a gene that encode protein.
Researchers using an antisense drug blocking APOC3 mRNA from Isis Pharmaceuticals demonstrated success in a study published in the New England Journal of Medicine two years ago, setting the stage for the emerging antisense era.