Gene therapy reduces high cholesterol in at-risk patients

People who suffer familial hypercholesterolemia, which is of genetic origin, have very high levels of LDL cholesterol (the “bad”), so they need continuous pharmacological treatment for life – through pills such as statins, which they take daily, or injections with different frequency. to control the problem. Additionally, they are more likely to suffer a heart attack at a young age.

A new study presented at the 2023 American Heart Association Scientific Sessions, held in Philadelphia between November 11 and 13, has shown that a single dose of one CRISPR-based gene editing therapy significantly decreased LDL cholesterol in people with this hereditary condition.

High levels of bad cholesterol contribute to the appearance of atherosclerotic plaques in blood vessels, which increases the risk of heart disease. In fact, if left untreated, people with this condition have 20 times greater risk of developing heart diseaseaccording to the American Heart Association.

The research results show the potential of a new therapeutic option to reduce LDL cholesterol for decades, said Dr. Andrew M. Bellinger, chief scientific officer of Verve Therapeutics, the company that developed this therapy, and lead author of the study. .

The investigational treatment VERVE-101 employs DNA editing technology to permanently deactivate the PCSK9 gene in the liver. PCSK9 is a gene that plays a key role in the control of blood LDL cholesterol by regulating the LDL receptor. The study just presented is the first trial in humans the VERVE-101.

Earlier this year, they were published in Circulation the results of the one-year study in animals. In this study VERVE-101 reduced PSCK9 levels between 67% and 83% and bad cholesterol between 49% and 69%, depending on the dose. After a single dose, reductions have now lasted 2.5 years, supporting the idea that VERVE-101 can potentially be an effective long-term or permanent treatment to combat elevated LDL levels.

Reduction of LDL cholesterol levels in at-risk patients

The ongoing study included seven men and two women in New Zealand or the United Kingdom with an average age of 54 years, all of whom were diagnosed with heterozygous familial hypercholesterolemiameaning they inherited a gene for the disorder from a parent, and their bad cholesterol levels were extremely high (with an average LDL cholesterol level of 201 mg/dL) despite taking the maximum tolerated dose of the medication to reduce LDL cholesterol.

“These numbers are consistent with the fact that, despite available treatments, only about 3% of patients living with heterozygous familial hypercholesterolemia worldwide have achieved treatment goals,” Bellinger said.

“Despite available treatments, only about 3% of patients living with heterozygous familial hypercholesterolemia worldwide have achieved treatment goals.”

Most participants had pre-existing severe coronary artery disease and had already suffered a heart attack, or had undergone coronary bypass or stent surgery to allow adequate blood flow to the heart muscle. None were taking PCSK9 inhibitors while they were in the study.

Each participant received a single intravenous infusion of VERVE-101, with the first cohort (n=3) receiving a low dose of 0.1 mg/kg and other cohorts receiving increasing doses, after consultation with an independent safety monitoring board. . The highest dose received was 0.6 mg/kg.

The results showed that higher doses of VERVE-101:

  • They achieved a reduction in LDL (bad) cholesterol by 39% and 48% in the two participants who received 0.45 mg/kg of the drug, and 55% in the only participant who received 0.6 mg/kg.

  • Blood PCSK9 protein levels decreased by 47%, 59%, and 84% in the three participants who received the 0.45 mg/kg or 0.6 mg/kg doses.

  • A reduction in LDL cholesterol occurred at six months in the only participant who received 0.6 mg/kg, with ongoing follow-up.

Among the study’s limitations, it stands out that it is a provisional report with few participants and that none of them received an alternative treatment that would allow a comparison. The results were measured by reductions in LDL cholesterol and not by changes in the occurrence of heart attacks, although LDL lowering is a well-known and validated variable among patients with heterozygous familial hypercholesterolemia and coronary artery disease. Studies with larger numbers of patients and a control group are needed to fully document the efficacy and safety of VERVE-101, Bellinger concludes.


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