In a groundbreaking development, the first trial of the gene-editing technique known as base editing has demonstrated promising results in reducing cholesterol levels. The trial, conducted by Verve Therapeutics in the United Kingdom and New Zealand, involved injecting participants with the treatment VERVE-101, designed to permanently deactivate the PCSK9 gene in the liver. PCSK9 regulates low-density lipoprotein (LDL), or ‘bad’ cholesterol, a significant contributor to heart disease.
Verve Therapeutics reported that a single injection of VERVE-101 led to a reduction of up to 55% in LDL levels in trial participants who had a condition causing lifelong high LDL. The base editing approach, using CRISPR-Cas9 machinery, makes precise edits to the gene without breaking the DNA’s double strands, offering a more targeted and potentially transformative treatment.
While the results are promising, the trial faced criticism due to safety concerns. Two serious adverse events, including one participant’s death from a heart attack five weeks after receiving VERVE-101, raised alarms. Despite the promising outcomes, Verve’s share price plummeted by nearly 40%, reflecting the market’s reaction to the safety issues.
The treatment’s side effects included brief flu-like symptoms and a temporary increase in liver enzymes, which returned to normal within days. The two cardiovascular events were deemed by an independent safety board as expected in individuals with advanced heart disease and not directly related to the treatment.
The base editing technique in VERVE-101 involves making a single-letter change to the PCSK9 gene sequence, permanently deactivating it and reducing LDL levels. While the results show a significant reduction in LDL, the long-term effects and potential ‘off-target’ edits elsewhere in the genome remain unknown.
Verve Therapeutics aims to select the best therapeutic dose from the trial and plans to launch a phase 2 trial in 2025. The company must follow trial participants for 14 years, as mandated by the US Food and Drug Administration for gene-editing therapies, emphasizing the critical importance of safety in such transformative treatments.
The trial marks a significant step in the potential use of base editing for addressing genetic factors contributing to cardiovascular diseases, offering a new avenue for treating conditions like high cholesterol with a single, precise intervention. However, the safety concerns highlight the need for thorough evaluation and monitoring in the ongoing development of gene-editing therapies.
Reference: https://www.nature.com/articles/d41586-023-03543-z
