Gene Therapy Targets Early Heart Attack, Stroke Risk

An interim report shows that a single infusion of gene-editing therapy substantially reduced an inherited form of high cholesterol.

Familial hypercholesterolemia (FH) is an inherited genetic disorder that causes dangerously high levels of low-density lipoprotein cholesterol (LDL-C). The condition affects about 1.3 million people in the United States and can lead to heart disease, heart attack, or stroke at an early age if left untreated.

When the condition is inherited from both parents, it is called homozygous familial hypercholesterolemia (HeFH) and is less common and more severe. Despite the availability of wide-range cholesterol-lowering medications, only about 3% of HeFH patients globally have reached optimal LDL cholesterol levels.

VERVE-101, a CRISPR-based gene-editing therapy, may offer new hope for people with HeFH, as its single infusion significantly reduced LDL levels, according to an interim report presented at the American Heart Association’s Scientific Sessions 2023 that took place on November 11 to 13 in Philadelphia.

"Instead of daily pills or intermittent injections over decades to lower bad cholesterol, this study reveals the potential for a new treatment option – a single-course therapy that may lead to deep LDL-C lowering for decades," said senior study author Andrew M. Bellinger, M.D., Ph.D., chief scientific officer at Verve Therapeutics in Boston, in a statement.

Bad cholesterol reduced by up to 55%

VERVE-101 uses DNA-editing technology to permanently turn off the PCSK9 gene in the liver. The gene plays a critical role in controlling blood LDL-C through its regulation of the LDL receptor.

The first human trial of VERVE-101 included seven men and two women who were 54 years old on average. Eight of them were white, and one was Asian. Each participant was diagnosed with HeFH and had extremely high LDL cholesterol levels, with an average measure of 201 mg/dL.

Optimal LDL cholesterol levels for people without heart disease are less than 100 mg/dL. For those with heart diseases, the recommended levels are below 70 mg/dL and up to 55 mg/dL for HeFH patients who already have severe heart disease.

The study participants were also taking the maximum-tolerated LDL cholesterol-lowering medication. Most of them had pre-existing severe coronary artery disease and had already experienced a heart attack or undergone coronary bypass surgery or stenting.

Each participant received a single intravenous infusion of VERVE-101. The first group received a low dose of 0.1 mg/kg, while other groups received escalating doses, with the highest amount of 0.6 mg/kg.

Two participants receiving 0.45 mg/kg of the drug saw their LDL-C levels reduced by 39% and 48%. The sole participant receiving the highest dose of 0.6 mg/kg had their bad cholesterol drop by 55%.

The therapy reduced blood PCSK9 protein levels by 47%, 59%, and 84% in the three participants receiving the 0.45 mg/kg or 0.6 mg/kg doses. The drug also reduced LDL-C at six months in the sole participant receiving 0.6 mg/kg, with follow-up ongoing.

Symptoms of familial hypercholesterolemia

One of the main symptoms of familial hypercholesterolemia is LDL cholesterol levels over 190 mg/dL in adults and over 160 mg/dL in children.

The physical signs of the condition may include:

• Bumps or lumps around knees, knuckles, or elbows
• Swollen or painful Achilles tendon
• Yellowish areas around your eyes
• A whitish-gray color in the shape of a half-moon on the outside of the cornea

Moreover, most people with FH have a family history of early heart disease or heart attack.

If the new gene-editing therapy VERVE-101 is found to be safe and effective, a single dose may have benefits lasting for decades.