Cardiovascular diseases could be among the world’s first medical conditions to be treated by changing a patient’s genes. If ongoing phase 3 trials succeed, gene editing will offer a novel therapy for transthyretin amyloidosis, and treatments for hyperlipidemia may not be far behind.
Precise gene editing using clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) was discovered in 2012. The discovery triggered worldwide efforts to apply the technology to correct gene-based diseases. But, to date, the FDA and the European Medicines Agency have approved only one gene editing therapy, for sickle cell disease.
“It’s an exciting time — to move from our current paradigm, which is long-term disease management with repetitive pharmacologic therapies, to where you could do a one-time treatment,” said Amrut Ambardekar, MD, a cardiologist at the University of Colorado Anschutz in Aurora, who chaired the writing committee for the 2026 American College of Cardiology (ACC) Scientific Statement on Gene Editing Therapy in Cardiovascular Disease.
Gene editing therapy differs from other gene and cellular therapies already in use, such as chimeric antigen receptor T-cell therapy that reprograms the patient’s immune cells to fight certain types of cancer and gene-silencing treatments that prevent the production of proteins encoded by a gene without changing the gene itself. By contrast, gene editing therapy changes DNA by inserting, deleting, or replacing sequences.
The main advantages are a single treatment that corrects the problem for life and — if phase 1 trial results hold — few adverse effects.
Gene Editing for ATTR
Transthyretin amyloidosis (ATTR) is an ideal first target for gene editing, said Marianna Fontana, MD, PhD, a cardiologist with the National Amyloidosis Centre at University College London. She is involved in trials of gene silencing and gene editing for this rare and debilitating disease in which the transthyretin protein misfolds, causing amyloid clumps. ATTR can lead to cardiomyopathy or polyneuropathy, or both. Before 2018, she said, the only treatment involved stabilizers that prevent the protein from clumping.
Gene-silencing drugs introduced at that time provided proof of concept, Fontana said, as well as evidence of the effectiveness and safety of genetic approaches. But these drugs need to be infused every 3 months.
Gene editing is a good approach for ATTR for several reasons, she said. The condition is caused by a single protein, and knocking down the protein is likely to be beneficial.
The protein is produced in the liver, and there is a current vehicle to deliver CRISPR-Cas9 to the organ: lipid nanoparticles. “We can target the liver extremely effectively,” she said.
ATTR and hyperlipidemia both involve protein production in the liver, Ambardekar said. “Right now, there are lipid nanoparticles that tend to naturally accumulate in the liver that can be given intravenously, and they tend to stay in the liver.”
This ability target the liver is one reason why gene editing for liver-based diseases is more advanced than for illnesses in other organs, including the heart, he added.
Furthermore, Fontana said, years of experience with gene-silencing drugs show genetic approaches to ATTR are probably safe.
Emerging Evidence
Together, these biological and technical factors check all the boxes for gene editing. “You wouldn’t edit the DNA if you didn’t know all those conditions were true,” Fontana said.
Phase 1 studies have shown safety and efficacy of editing a gene to permanently inactivate the gene, stopping production of the faulty protein at its source. The fix has been effective in these small studies in both hereditary and wild-type ATTR with cardiomyopathy and in hereditary ATTR with polyneuropathy.
Two phase 3 studies (MAGNITUDE and MAGNITUDE-2) are under way. Both were paused after evidence of hepatic toxicity emerged “in a tiny proportion of patients,” Fontana said. “We need to understand the reasons for the hepatotoxicity. I’m very confident we will find a way to overcome that problem.”
The hold on MAGNITUDE-2 has been lifted, and Fontana is confident MAGNITUDE will also restart soon.
Gene Editing for Hyperlipidemia
Gene editing is similarly safe and effective in treating hyperlipidemia, including both high LDL cholesterol and high triglycerides, said Steven Nissen, MD, chief academic officer of the Heart, Vascular, and Thoracic Institute of the Cleveland Clinic. In a phase 1 study targeting the angiopoietin-like protein 3 gene (ANGPTL3), editing succeeded in reducing these lipids by about 50%. “This is the first CRISPR-based study that involved a lipid target,” Nissen said.
While some patients had familial hypercholesterolemia, some did not. The study showed that gene editing works as well in patients without a specific faulty gene. “If you have polygenic hypercholesterolemia, the phenotypic, which is high LDL [low-density lipoprotein], is the same,” Nissen said. “If you can inhibit something that interferes with lipoprotein lipase, it will lower LDL and triglycerides, regardless of whether you have the genetic defect.”
Gene editing can either stop a gene from producing a “bad” protein or kickstart a gene to produce a functional protein, Ambardekar said. “The holy grail is that it would be able to do both.”
The hyperlipidemia study showed risks associated with gene editing — infusion-related reactions and a death in a patient with advanced coronary disease almost 6 months later — but a singular benefit.
“If you give a statin to patients, 50% of them are not taking the drug a year later,” Nissen said. “The hope would be that if we can develop a single, one-and-done therapy that can fix the problem, then we can avoid the issues with long-term adherence to treatment.”
Risks to Watch
There is concern about gene editing affecting other genes, although studies in primates have shown no such off-target effects, Nissen said.
This risk is theoretical at this point, as is the risk for germline transmission to offspring, Ambardekar said. Risks connected to the delivery mechanisms have been observed, such as hepatotoxicity from lipid nanoparticles or infusion reactions in therapies that use an adeno-associated virus to deliver CRISPR-Cas9.
Gene editing therapy is so novel that the FDA is requiring a minimum 15 years of follow-up to see if any adverse effects develop long after treatment, according to the ACC statement. Such long-term effects could include cancer from gene editing interfering with tumor suppressor genes or oncogenes. It will take years to determine whether such risks emerge.
Medicine’s Next Frontier
The watchword is caution as gene editing moves into phase 3 trials. “We will have to be very vigilant and very careful,” Nissen said.
Ambardekar said enthusiasm for gene editing therapy must be balanced with “making sure therapies are efficacious as well as safe.”
None of the experts say they can forecast when new drugs will be approved and become available.
Researchers are conscious that gene editing represents medicine’s next frontier and needs to be accepted by patients and clinicians.
If the promising results hold, it’s important to get the treatments to the patients who will benefit, Ambardekar said, “ensuring that they’re equitably administered, so that people from all walks of life have access to these therapies.”
Ambardekar reported no disclosures. Fontana reported consulting for Alnylam, Alexion/Caelum Biosciences, AstraZeneca, BridgeBio/Eidos, Prothena, Attralus, Intellia Therapeutics, Ionis Pharmaceuticals, Cardior, Lexeo Therapeutics, Janssen Pharmaceuticals, Pfizer, Novo Nordisk, Bayer, and MyCardium. She receives research grants from Alnylam, BridgeBio, AstraZeneca, and Pfizer. She has share options in Lexeo Therapeutics and shares in MyCardium. Nissen reported consulting for Amgen and Glenmark Pharmaceuticals. He has received research grants from AbbVie, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, Eli Lilly and Company, Esperion Therapeutics, Mineralys, New Amsterdam Pharmaceuticals, Novartis, and Silence Pharmaceuticals. He has received travel coverage from Eli Lilly.
Carolyn Brown is a freelance scientific and biomedical reporter in Ottawa, Canada.
