VERVE-101’s biggest selling point is that it claims to be “once and for all” in preventing cardiovascular disease.
Writing |Ling Jun
Source | “Medical Community” Public Account
By “modifying” the human body’s specific genetic code at the molecular level, the advent of gene editing technology seems to bring infinite possibilities for mankind to overcome diseases.
On July 12, Verve Therapeutics, an American biotechnology company, announced that its base-editing therapy VERVE-101 had been dosed in New Zealand for the first time. This is the world’s first clinical trial of in vivo base editing, and unlike existing therapies, it claims to prevent cardiovascular disease once and for all.
This therapy is not difficult to understand in principle: through gene editing technology, a “bad gene” in human beings can be directly turned off to eliminate the pathogenic factors at the root. As early as 3 years ago, Dr. Sekar Kathiresan, one of the founders of the company, made a high-profile claim: If proven safe and effective, it is the answer to preventing and treating heart disease.
Potential ‘game-changing’ gene editing
Low-density lipoprotein cholesterol (LDL-C) is a common indicator in physical examinations, known as “bad cholesterol”, and is an important factor in atherosclerotic cardiovascular disease (ASCVD). precipitating factors.
It is estimated that nearly 40 percent of U.S. adults have elevated LDL-C levels, which can block blood vessels and potentially lead to heart attack, stroke, or heart failure.
Under normal circumstances, low-density lipoprotein receptor (LDL-R) binds to low-density lipoprotein (LDL) and transports it to the liver for degradation, preventing high LDL-C levels . But humans have a gene called PCSK9 that expresses the PCSK9 protein, which binds to LDL-R in the liver and degrades it.
In layman’s terms, LDL-C is one of the important risk factors for cardiovascular disease, and LDL-R is a natural weapon against it, but now the PCSK9 protein has destroyed the “weapon” . The newly developed VERVE-101 base editing therapy is to eliminate the PCSK9 gene.
The reason why it is called “once and for all” is that the current drugs can only control “blood lipids” and require long-term and regular use. . “But VERVE-101 has the potential to be a game-changer, transforming the traditional chronic care model into a single-course, lifetime treatment solution,” said Dr. Kathiresan.
VERVE-101 uses base editing therapy technology.
In the field of traditional gene editing, CRISPR/Cas9 gene editing accurately cuts DNA double strands, first removes an “unwanted” gene sequence, and then relies on the cell’s own repair mechanism to correct the gene , thus completing the “treatment” process. But DNA double-strand breaks can lead to unpredictable results in gene-edited cells.
Source: The New York Times
Based on this, base editing technology was born. Compared with cutting off the DNA double-strand “dramatically”, base editing can accurately convert a single nucleotide into another nucleotide to complete the DNA editing task.
From “knock out a gene sequence” to “modify a single DNA letter,” VERVE-101 base editing therapy replaces a single base “A” in the PCSK9 gene sequence with a “G” , permanently inactivating this “bad gene”. Preclinical animal experiments released in 2021 show that a single dose of VERVE-101 can reduce “bad cholesterol” levels by 60%, with a good safety profile and remains stable to date.
In a new human clinical trial this month, VERVE-101 targets patients with heterozygous familial hypercholesterolemia (HeFH), whose cholesterol levels are often It is twice as high as the average person and is also at a high risk of cardiovascular disease.
However, the company believes that once the initial trials are successful, the range of editable target genes will be further rolled out in the future, including the 31 million patients with hereditary ASCVD worldwide, and the same technology can eventually be used for hundreds of millions of people. plan to protect them from heart attack.
According to relevant data, about 2.4 million people die from ASCVD every year in my country, accounting for about 61% of all cardiovascular deaths.
Editing the Book of Life
Gene editing technology dates back to the 1980s.
At the time, microbiologists discovered a special piece of DNA in bacteria that later became known as CRISPR. In the history of fighting against viruses, bacteria have evolved the CRISPR-Cas9 system, which can transfer the invading virus genes from their ownexcised on its own genome.
In the 20th century, American scientist Doudna and French scientist Charpentier realized when they were studying CRISPR that the working principle of the system might allow them to precisely cut out a selected DNA sequence .
In June 2012, two scholars published a landmark paper in human history in the journal Science: “Programmable, dual RNA-guided DNA endonucleases in adaptive bacterial immunity. Enzymes”, the door to gene editing was completely opened, and they won the 2020 Nobel Prize in Chemistry for this.
Now, in cancer research, for example, gene editing techniques can systematically alter every gene in a cancer cell, allowing scientists to investigate which genes are involved in the development of cancer.
In the field of blood diseases, researchers have used CRISPR to snip out the “switch” that turns off the gene for fetal hemoglobin, so they can develop into hemoglobin-rich red blood cells. Results of the latest clinical trial published this year showed that 42 of 44 beta-thalassemia patients treated with gene editing no longer required regular blood transfusions.
Source: Medicine Rubik’s Cube
But as mentioned earlier, “sniping” DNA double-strands has unknown safety implications. On this basis, in 2016, Chinese American scientist Liu Ruqian and his team developed a single-base editor that can convert G·C base pairs into T·A base pairs. In 2017, the exchange of A·T and G·C was realized.
The directional modification of a single base can be achieved without relying on DNA double-strand breaks. If CRISPR-Cas9 is “scissors”, then base editing is “rubber” , Liu Ruqian was also named “Top Ten Scientific Figures Influencing the World in 2017” by Nature. In 2019, Liu Ruqian and his team stated in a paper that base editing technology could theoretically repair over 65,000 known pathogenic human genetic variants.
It is worth mentioning that the delivery technology used for VERVE-101 into the body this time is the same as the new coronavirus mRNA vaccine, which uses a lipid nanoparticle (LNP) carrier. In 2020, mRNA vaccines were approved and put into large-scale use around the world, which greatly promoted the development and maturity of LNP technology.
“A New Hope”
In recent years, the development of gene editing technology in the medical field has been in full swing, but most of them are for rare or genetic diseases for which there is no effective treatment. VERVE-101 is hailed as a “new milestone”, and because it targets common cardiovascular diseases, it is considered a key step toward “universalization” of gene editing therapy.
However, Professor Zhou Peng’s analysis of the “medical community” shows that, in general, the “frontier concept” of VERVE-101 is higher than the actual value. This concern is consistent with the views of many overseas scholars on VERVE-101.
According to Zhou Peng, to control blood lipids, traditional cheap statins are very cost-effective. No single drug or therapy has yet been proven to completely replace statins, even though they may be taken for life.
For statin-resistant patients, or some patients whose blood lipids are still poorly controlled after medication, in addition to ezetimibe, there are currently two types of cutting-edge PCSK9 inhibitors—monoclonal antibodies And siRNA drugs have entered the clinic or the market one after another. Based on the combination with statins, they have been proven to be safe and effective.
In contrast, the biggest selling point of VERVE-101 may be that it claims to be able to prevent cardiovascular disease once and for all. In this regard, Professor Zhou Peng is even more cautious.
“Including atherosclerosis, controlling LDL-C levels alone does not mean that it can permanently eliminate the possibility of cardiovascular disease attacks. Smoking, hypertension, diabetes, obesity, etc. are all important for ASCVD Risk factors.” Professor Zhou Peng introduced that a study showed that the combination of PCSK9 inhibitors on the basis of statins can further reduce LDL-C levels by about 50%, but the absolute benefit only increases within a limited follow-up time. 2%.
“The limited clinical benefits of ezetimibe, PCSK9 inhibitors, etc. are all based on statins. From animal experiments, VERVE-101 will reduce ‘bad cholesterol’ It has been reduced by 60%, although the magnitude is very large, but it does not surpass other PCSK9 inhibitors.” Professor Zhou Peng believes that for high-risk groups of ASCVD, VERVE-101 only provides an additional treatment option. In addition, the cost-benefit ratio is also a concern.
Bloomberg estimates that current VERVE-101 therapy could cost between $50,000 and $200,000 per patient.
In terms of long-term safety, MIT Technology Review issued a document stating that there have been cases of side effects such as muscle pain due to the reduction of PCSK9 protein. Common drugs can be stopped in time, but it is not so easy to modify after gene editing.
Professor Zhou Peng called VERVE-101 and similar technology products “a new hope”, “but it cannot be exaggerated”, “I think that even if it makes great progress all the way and finally goes on the market, the problem of ASCVD will be solved. It’s impossible to solve it completely.”
It is reported that another gene editing project under Verve’s company is also under development, targeting the ANGPTL3 gene. As a key regulator of cholesterol and triglyceride metabolism, ANGPTL3 has emerged as one of the most promising targets for the treatment of severe hyperlipidemia.
Professional Profile
Beijing Mingde Hospital Cardiovascular Disease Specialist, Director of Internal Medicine, attending physician and senior second-level/senior manager of the Department of Internal Medicine of BOE Technology Group.
Successfully engaged in scientific research in the Department of Physiology, Milton S. Medical Center, Pennsylvania State University, and the Heart Center of Wake Forest University School of Medicine for 7 years, and engaged in clinical cardiovascular disease in China. He has worked for 18 years and is good at the diagnosis and treatment of common diseases, frequently-occurring diseases and critically ill patients in the cardiovascular field.
Main academic part-time jobs:
Member of the Resuscitation Medicine Group of the 9th Emergency Medicine Branch of the Chinese Medical Association
The first member of the ECG and Heart Function Branch of the Chinese Geriatrics Association
Member of the Standing Committee of the Second Cardiac Rehabilitation Professional Committee of the Cross-Strait Medical and Health Exchange Association
Vice-Chairman of the High-alert Drugs Management Professional Committee of the Chinese Medical Education Society
Editor-in-Chief of Journal of Cardiovascular Disease Research (JCDR)
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