Introduction
Many people suffer from high levels of LDL cholesterol in their blood, which is considered the “bad” cholesterol that clogs arteries. Among these individuals, patients with familial hypercholesterolemia experience a genetic disorder that dramatically increases levels of LDL cholesterol in the blood. This condition can lead to serious heart diseases at an early age or even death. To address this issue, a team of researchers has trialed a new gene-editing treatment called VERVE-101, which aims to stop the function of a gene that raises cholesterol levels. Initial results from the trial have shown that VERVE-101 successfully reduced LDL cholesterol levels significantly. This is the first time the effect of DNA modification within a human body has been demonstrated in such a way. This treatment is promising for patients with familial hypercholesterolemia who suffer from lifelong symptoms and require continuous medication. This new therapy could change the treatment strategy for these patients.
VERVE-101 Technology Relies on a DNA-Editing Protein
The VERVE-101 technique consists of two types of RNA molecules – molecular cousins of DNA – packaged inside a lipid bubble. When the drug is injected into the bloodstream, it travels to the liver and integrates into cells. One RNA molecule instructs the cells to build a protein called an adenine editor. The other molecule acts as a genetic GPS, guiding the editor protein to the correct part of the DNA. The PCSK9 gene, which contains instructions for producing a protein that increases cholesterol levels in the blood, is shut down with a single modification at a specific location within the gene. The modification is completed within a week, and the drug breaks down quickly. After a few weeks, VERVE-101 disappears from the body, leaving only the genetic change made in the PCSK9 gene.
PCSK9 is an Attractive Target for Gene Editing Treatment
PCSK9 has been a crucial target for the past decade, as researchers know that some people possess mutations in the PCSK9 gene that effectively disable it. Researchers have observed that these individuals have lower levels of LDL cholesterol and significantly fewer heart diseases. This pioneering study has advanced the field, as scientists now have evidence that people can live healthily when the PCSK9 gene is disabled. This makes it a “very attractive drug target,” as it suggests that disabling PCSK9 would cause no harm and may even help reduce the risk of heart disease. Typically, the PCSK9 protein works to degrade another protein known as the LDL receptor. This receptor is one of the champions; it maintains the balance of bad cholesterol in the blood by capturing it from the bloodstream and transporting it to liver cells for disposal. Without sufficient LDL receptors, LDL cholesterol levels in the blood rise.
Early Clinical Trial Results for VERVE-101 Reveal Potential Benefits and Risks
The Kathiresan team injected a single dose of VERVE-101 intravenously into 10 individuals with familial hypercholesterolemia, most of whom suffer from severe heart disease. In those who received the highest tested doses of the drug, LDL cholesterol levels plummeted acutely by 39 to 55 percent. The decrease appears to be long-lasting, as the LDL cholesterol levels of the patient who received the highest dose remained stable for 180 days following the injection of VERVE-101 into the bloodstream. Pelinger described the results as “almost what we expected and planned for,” based on the team’s previous findings in non-human primates. However, the new data from patients, although preliminary, puts the drug on the brink of something larger. “This opens the door to a completely new way of treating heart disease,” says Kathiresan. The future use of VERVE-101 will depend on its safety. During the trial, the team noted some potential red flags. Four patients reported mild reactions to the intravenous injection, including headaches and slight fever. But at the cardiology meeting, attention focused on something more serious. The day after the injection, one patient suffered a heart attack. Five weeks post-injection, another patient’s heart suddenly stopped beating. This situation resulted in death due to the patients’ underlying heart disease, according to an independent data monitoring committee that investigated the cases. However, the heart attack may be linked to the treatment, as it occurred shortly after the dose, according to the committee’s assessment. However, Kathiresan notes that the patient had been experiencing chest pain before the study and did not inform investigators. These are considered “very sick patients,” according to cardiologist Topp. She believes such patients should be excluded in future trials with the drug.
Plans
For the Future
Verve plans to enroll more patients at the highest two doses to determine which dose to move forward with. Researchers also plan to test a second version of the drug, VERVE-102, which uses a different type of fat. Depending on these results, Verve intends to transition one of the drugs into a larger clinical trial in 2025. If successful in individuals with familial hypercholesterolemia, the company intends to expand to include a broader group of patients, including those without the genetic disorder. Katheresan says that developing new drugs takes a long time and may take over a decade to become a drug that doctors can prescribe. Verve launched the PCSK9 editing project in 2018, and Katheresan hopes to have an approved drug by the end of this decade.
VERVE-101 is one of several gene-editing drugs in clinical trials
One potential side effect of gene-editing treatment is unintended modifications to DNA. VERVE-101 targets the PCSK9 gene, but what if it strays to another location in the genome? asks Ann Goldberg, an endocrinologist at the Washington University School of Medicine in St. Louis. “The technology looks really interesting,” she says, “but we need more data.” A change in DNA in the wrong place could put people at risk of cancer. Bellinger said, “We believe this risk is very low” with VERVE-101. According to him, most of the company’s work focuses on proving that it does not make modifications elsewhere in the genome. Current editing drugs – including those used in VERVE-101 – have improved significantly since the early days of the technology. They are characterized by having high editing efficiency at the specific target in the DNA with minimal editing of the unspecified target. Currently, there are five other clinical trials for base editing targeting other diseases such as sickle cell disease and leukemia. Liu hopes that gene editing agencies will give patients “a whole new chance at life.” Katheresan’s team considers VERVE-101 a one-time health procedure, like “molecular surgery without a scalpel.” In theory, the modification made by VERVE-101 can be reversed, but that’s not what he and his colleagues envision. For cardiologist Lloyd-Jones, who did not participate in the trial, the dream is to offer people with familial hypercholesterolemia a treatment that does not rely on taking a statin pill daily. He said, “This treatment could be an option they seriously consider.”
Source: https://www.sciencenews.org/article/verve-101-gene-editing-ldl-cholesterol-base-editing
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