Gene Editing and Cholesterol: The Road Less Traveled

The cruise control on my car recently went out. More accurately, the cruise control button on my car broke. I can push it in, but unless I manually hold it in all the time, it just releases, and the cruise control disengages. My workaround has been to wedge a penny between the cruise control button and the steering wheel every time I want to use cruise control. It’s crude, annoying, and probably dangerous at some level. The solution is clear: I need to fix the button. An obvious solution, however, is not necessarily an easy one. To be honest, I don’t even know if I can buy a replacement button, not to mention I’d have to remove the steering wheel, take apart the insides, and avoid having the airbag blow up in my face. A similar dynamic presents itself with defective or overactive genes: the solution is obvious, but the fix is complicated, difficult to implement, and requires considerable care to mitigate risks.

The obvious solution to genetic problems is to fix the genes. Before we cruise into what that entails, let’s quickly travel back to biology 101: What are genes? Genes are small segments of DNA that meet two criteria: they are inherited from parents and they relate to specific traits or characteristics. A classic example is eye color: you inherit eye color from your parents, and specific genes determine this characteristic. Not all genes code for things you can see; some code for the shape of blood cells, hormones, cholesterol proteins, and so on. But let’s quickly shift into reverse; what does “code for” mean? DNA is a very long strand of nucleotides, the building blocks of DNA. Nucleotides are arranged in long strands that the body can “decode” and use to build proteins that make up things like eye color or hormones.

Back to the main road: when genes malfunction, most medicines target the protein products rather than the genes themselves. They are like shoving a penny in the steering wheel: crude, annoying, and probably dangerous at some level. Gene editing, on the other hand, addresses the root problem by correcting the DNA errors themselves.^[1] The methods we have today can either insert new DNA or change the existing DNA code.^[1] DNA insertions (called gene transfer) can replace dysfunctional genes.^[1,2] Editing the DNA code can fix coding errors in the genetic code, making a dysfunctional gene functional, or can silence overactive or dangerous genes.”^[1,2] Either way, gene editing is a permanent change to genes that solves problems for life.^[1] This means no more shoving pennies in the button, but also means there are no takesies-backsies. Just like when repairing the steering wheel, we have to be extra careful not to “set off the airbag” by making unintended changes. It also means the risks are high and must be outweighed by the disease they target.

One disease under serious investigation for gene therapies is high cholesterol, also called hypercholesterolemia: hyper- meaning “high,” cholesterol obviously meaning “cholesterol,” and -emia meaning “presence in blood.” High cholesterol presence in blood is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of death in the United States.^[3] In general, cholesterol in our body has to be driven to cells for use as energy and for building and maintaining cell structures. The delivery vehicle is a lipoprotein, a combination of a fatty lipid and a structural protein. Low-density lipoprotein (LDL) is the end product of this delivery chain and must be taken up by the liver via LDL receptors, allowing the liver to recycle, store, and repackage cholesterol.^[4] When there is too much LDL in the bloodstream, the fats can build up in the blood vessels. This buildup can narrow the vessels and increase the risk of heart attack, mini-stroke, stroke, chest pain, and other problems.^[1,4]

High cholesterol is a good target for gene therapies for two big reasons: it leads to ASCVD, the #1 killer of Americans, and there are genetic conditions that predispose people to hypercholesterolemia.^[3,4] Those with genetic conditions have familial hypercholesterolemia, which is rare but difficult to treat with current medications.^[4] In this population, the problem is that a gene responsible for the reabsorption of LDL into the liver malfunctions.^[4] There are actually a few different possible genetic mutations, which have given scientists valuable insight into different targets for medical and genetic therapies. Some mutations include:^[4,5]

• The LDL receptor protein itself can lose function, inhibiting LDL reabsorption.
  • 90% of familial hypercholesterolemia cases
• A protein on the lipoprotein delivery vehicle, APOB100, can mutate, interfering with reabsorption.
  • 5% of familial hypercholesterolemia cases
• PCSK9, a protein that recycles LDL, can become too active.
  • Fewer than 1-5% of cases
• Other, rarer gene mutations.

These genes, therefore, are excellent targets for gene therapies, especially for those with familial hypercholesterolemia. Gene therapy techniques include breaking the DNA strand to make repairs (CRISPR-Cas-9), editing nucleotides without breaking the DNA strand (base editing), introducing new RNA to be copied into the strand (prime editing), and editing the mechanisms that determine which genes are turned into proteins (epigenome editing).^[2] If this all sounds like a complicated spaghetti junction of techniques, that’s because it is! These are complex, expensive tools that have been developed to maximize the likelihood that the correct genes - and only the correct genes - are changed. A lot of preclinical research has been done to make sure these tools can reach the target genes, produce consistent changes, and avoid altering other genes to mitigate off-target effects.^[6] Now we are getting to the point where the tools are safe enough to try tackling diseases like familial hypercholesterolemia, and eventually overtake high cholesterol in those without genetic differences. This takes a lot of time, care, effort, volunteers, and, of course, research, because gene editing is a one-shot deal and you really don’t want that airbag to blow up in your face.

Creative Director Benton Lowey-Ball, MWC, BS, BFA

References:

[1] Hoekstra M, Van Eck M. Gene editing for the treatment of hypercholesterolemia. Current Atherosclerosis Reports. 2024 May;26(5):139-46. https://doi.org/verve10.1007/s11883-024-01198-3

[2] Stankov S, Cuchel M. Gene editing for dyslipidemias: New tools to “cut” lipids. Atherosclerosis. 2023 Mar 1;368:14-24. https://doi.org/10.1016/j.atherosclerosis.2023.01.010

[3] Centers for Disease Control and Prevention. Cardiovascular disease. Centers for Disease Control and Prevention website. Published June 3, 2024. Accessed March 12, 2026.  https://www.cdc.gov/cdi/indicator-definitions/cardiovascular-disease.html

[4] Canepari C, Cantore A. Gene transfer and genome editing for familial hypercholesterolemia. Frontiers in Molecular Medicine. 2023 Apr 3;3:1140997. https://doi.org/10.3389/fmmed.2023.1140997

[5] Zhao H, Li Y, He L, Pu W, Yu W, Li Y, Wu YT, Xu C, Wei Y, Ding Q, Song BL. In vivo AAV-CRISPR/Cas9–mediated gene editing ameliorates atherosclerosis in familial hypercholesterolemia. Circulation. 2020 Jan 7;141(1):67-79. https://doi.org/10.1161/CIRCULATIONAHA.119.042476

[6] Horie T, Ono K. VERVE-101: a promising CRISPR-based gene editing therapy that reduces LDL-C and PCSK9 levels in HeFH patients. https://doi.org/10.1093/ehjcvp/pvad103