RNA editing makes a protective gene variant available to patients who lack it naturally

A rare gene variant as a blueprint

It has long been known that some people carry a naturally occurring variant of the gene B4GALT1, which controls an enzyme involved in the glycosylation of proteins circulating in the blood. This variant, enriched within the US Amish community, is associated with lower LDL cholesterol and lower fibrinogen, and with reduced cardiovascular risk.

B4GALT1 plays a central role in how the body glycosylates apolipoprotein B, LDL and fibrinogen, which in turn governs how quickly these are cleared from circulation. The question ProQR and TNO set out to answer: can this protective trait be induced in people who do not carry the variant naturally, without permanently altering the DNA?

Editing RNA instead of DNA

The answer lies in RNA editing, a technology that does not modify the DNA itself but rather the messenger RNA (mRNA), the intermediate molecule that carries the genetic code from DNA to the cell’s protein-making machinery. Using a short, chemically modified oligonucleotide, the body’s natural RNA editing system is guided to make one precise edit in the B4GALT1 mRNA. The result: the enzyme temporarily takes on the properties of the protective variant, while both the amount of enzyme produced and the underlying DNA sequence remain unchanged.

That sets the approach apart from, for instance, gene therapy or RNA techniques that silence a gene altogether, such as siRNA. Where gene silencing is essentially ‘all or nothing’, RNA editing allows for a fine-tuned, reversible adjustment of enzyme activity, precisely the kind of graded intervention required for an enzyme whose complete loss causes serious disease in humans, while partial inhibition is protective.

Why this model carries weight

A key strength of the study lies in its design: effects were consistently benchmarked against a placebo-treated control group, in one of the most clinically relevant translational models available for cardiovascular and lipid-lowering drug research. The model responds reliably to medications already used in the clinic, including statins and PCSK9 inhibitors, which strengthens confidence in the translation of these findings towards humans.

TNO Metabolic Health Research carried out this part of the study, contributing expertise in lipid and lipoprotein metabolism and translational modelling for cardiometabolic disease.

What still needs to happen before this reaches patients

The results are encouraging, but the path to the clinic remains long. The current study was not designed to measure whether treatment reduces plaque formation in blood vessels, that requires longer-term follow-up studies. Nor has reversibility been studied in detail: how quickly the effect disappears once treatment stops, even though reversibility is one of RNA editing’s key theoretical advantages over permanent gene-editing approaches. In addition, the current delivery method (lipid nanoparticles) is not yet optimized for chronic use in cardiovascular indications; development of a liver-targeted delivery system is cited as a necessary next step.

Finally, dosing precision is essential. In humans, complete loss of B4GALT1 activity causes a serious congenital disorder, whereas partial inhibition of around 50%, as seen in carriers of the natural protective variant, is protective. That makes a precisely tunable intervention, of the kind RNA editing enables, fundamentally different from an approach that switches a gene off entirely.

A new starting point for precision medicine

The publication illustrates a broader shift underway in genetic medicine: from correcting disease-causing mutations towards introducing evolutionarily advantageous variants into people who do not carry them naturally. For cardiovascular disease, this points to a possible complement to existing lipid-lowering drugs, aimed specifically at the residual risk that remains even after optimal treatment with statins or other agents.

For the sector, the follow-up question is not only one of efficacy, but of scale-up: which delivery route is suitable for chronic use, how is long-term safety monitored, and what regulatory pathway applies to a technology that modifies RNA rather than DNA? For researchers and developers looking to explore this route further, TNO’s validated preclinical test system offers a starting point for benchmarking new RNA-editing candidates before they reach the clinic.

Get in touch with TNO Metabolic Health Research to explore how translational models can support the development and validation of new RNA-targeted cardiovascular therapies.