A step forward for genomic-based medicine

The world’s Covid response has benefited from the twenty-odd years of large-scale genetics research that preceded it: inexpensive, widely-available PCR and sequencing; mRNA synthesis and delivery.  None of that was the plan, though.  Genomics was supposed to produce widely-applicable treatments for diverse medical problems, and revolutionise medical diagnosis and treatment. It didn’t: there have been genuine breakthroughs, but mostly in the  form of expensive treatments for rare diseases.

Today in Britain, there was definite progress.   NICE, who make recommendations for medication subsidy decisions, have pushed for the funding of inclisiran in people who have high cholesterol and who’ve already had a stroke or heart attack.  Inclisiran lowers LDL (‘bad’) cholesterol a long way, by a different mechanism from the current ‘statin’ drugs, and it can be given by twice-yearly injection at a GP’s office. The drug would usually cost more than it’s worth, but the NHS has a Pharmac-like secret deal to pay less than the £2,000 sticker price.

I’m not sure this is huge news from a public health point of view, but it’s interesting to someone who has worked in genetic epidemiology.  Inclisiran inhibits a gene called PCSK9.  The function of PCSK9 was originally fairly obscure; mutations in it were found by genetic linkage analysis to be related to familial high cholesterol in a group of families who didn’t have mutations in the known high-cholesterol genes.  Research in the Dallas Heart Study, a cohort study of risks for heart disease, found that several people with unusually low cholesterol also had mutations in PCSK9, suggesting that blocking the gene’s action would lower cholesterol.  Now, we actually need some cholesterol, so you’d worry that blocking the gene could be dangerous — but the Dallas Heart Study also found one woman who had natural mutations in both her copies of the gene, and who had extraordinarily low LDL cholesterol and no apparent adverse health effects.  All this came from largely correlational research that relied on inexpensive, large-scale gene sequencing — exactly what genomics had promised.

The other genetic aspect of the new treatment is that it works by silencing the gene, rather than the more-usual approach of blocking the activity of the enzyme after it has been produced.  Inclisiran is a ‘small interfering RNA’ molecule that binds to messenger RNA from the PCSK9 gene and triggers the cell’s recycling mechanisms to chop it up. The protein never gets produced.  This idea has been through hype and disappointment cycles — a small piece of RNA injected into the body looks remarkably like a virus, and the immune system tends to disapprove — but this time it seems to work, and to work on a common risk fact for a common disease.

The return on genetic ‘precision medicine’ has still been rather disappointing compared to the hype, but it’s nice to have the occasional example where it does basically work as promised.