A First: CRISPR-based Gene Editing Therapy for LDL Cholesterol Lowering In Humans | AHA Scientific Sessions

Ten people have been infused with a CRISPR-base gene editing therapy designed to lower LDL cholesterol levels in the first human trial of the therapy, the company developing the investigational treatment announced today at the American Heart Association (AHA) Scientific Sessions meeting in Philadelphia.

One of the study volunteers died from a cardiac arrest five weeks after infusion with the treatment, and another had a myocardial infarction with nonsustained ventricular tachycardia, Andrew M. Bellinger, M.D., Ph.D., the chief scientific of Verve Therapeutics, the Boston-based company developing the therapy, said during a press briefing about the therapy. The study volunteer that died had ischemic cardiomyopathy and an autopsy didn’t show any acute finding; “it was really the underlying disease” that caused the cardiac arrest, he said. After reviewing both cases, the data safety monitoring board recommending continuing the study without any changes, according to Bellinger.

The importance of safety was emphasized by the moderator of the press briefing, Donald M. Lloyd-Jones, M.D., M.Sc., a professor at Northwestern University’s Feinberg School of Medicine, and the expert discussant, Karol E. Watson, M.D., Ph.D., a professor of Medicine/Cardiology at the David Geffen School of Medicine at The University of California, Los Angeles.

“This a gene-editing study. You are changing the genome—forever,” Watson said. “Safety is going to be of the utmost importance, especially because there are currently safe and efficacious treatments for lipid lowering. This is a strategy that could be revolutionary but we have to make sure it is safe.”

Bellinger said preclinical animal studies have shown that a small amount of the gene therapy, which the company is calling VERVE-101, goes to the spleen and the adrenal glands but the vast majority goes to where it is supposed to, the liver. He also said the therapy homes in on a particular location in proprotein convertase subtilisin/kexin type 9 (PCSK9) genes in liver cells, changing a single base pair, thereby disabling the gene. “That’s where we put 95% of our work as a company, is demonstrating that we do not induce structural arrangements — we do not make edits elsewhere in the genome.”

Favorable results of animal studies of VERVE-101 were published in Circulation earlier this year, but today’s results were the first public announcement about what happens when the DNA-snipping therapy is given to people.

“This represents the first demonstration that a single DNA base pair change made in the body can cause a clinical benefit for patients,” Bellinger said.

The PCSK9 genes are a target for gene editing because the PCSK9 proteins they produce are instrumental, upstream regulator of LDL cholesterol.

Lloyd-Jones said PCSK9 is good genetic target because the track record of lowering or inhibiting PCSK9 proteins by other means hasn't produced notable adverse effects. Repatha (evolocumab) and Praluent (alirocumab) are FDA-approved monoclonal antibodies that inhibit PCSK9.

Data shared by Bellinger showed that VERVE-101 had little effect on PCSK9 or LDL cholesterol at lower doses but did have an effect at two higher doses.

At the highest dose (6 mg per kilogram of the patient’s body weight) LDL was reduced by 55% at 28 days after that reduction continued for 180 days after the infusion.

The patients enrolled in the study have an inherited genetic condition called heterozygous familial hypercholesterolemia that causes very high LDL levels and, consequentially, cardiovascular disease. According to the abstract describing the study, which listed nine patients not the 10 mentioned by Bellinger during the press briefing, the average LDL of the study volunteers was 201 mg/dL and three were unable to tolerate high-intensity statin therapy.

Bellinger said infusion reactions to the higher doses have been common, including headaches and mild body aches. Liver transaminase levels increased but returned to normal quickly, he said.

Bellinger noted that the gene-editing contents VERVE-101 are encapsulated in a lipid nanoparticle that gets pulled out of the blood by hepatocytes. Other gene therapies use viral vectors to deliver their contents. Delivery by lipid nanoparticle means that people could be retreated, he said. "Hypothetically if somebody 15 years later needed another treatment, they could safely get another treatment. But that's not what we are designing it for. We believe it should be lifetime therapy."

Bellinger positioned VERVE-101 as a potential treatment for heterozygous familial hypercholesterolemia, which affects about 1.3 million people in the U.S., according to a AHA press release about the study. He painted a picture of the gene-editing therapy as favorable alternative to decadeslong treatment with medications and "intermittent injections" that is only partly successful. However, Bellinger also said that VERVE-101 won't entirely end the need for medications.

"The goal is not to take people off effective therapies like statins that we know reduce mortality, " he said. "It's really about providing a durable solution that could underlie the core of their care over decades."