48 years old old sun can not think, long-term low blood pressure of their own suddenly soared to nearly 200; After that, in one breath on the fifth floor without effort, he every two floors have to stop to catch a long time, and then then climb up. Every day the medicine is endless, buck, fat reduction. Occasionally the pain is so bad that he contains a quick-acting heart-saving pill, gritting his teeth to endure.
Like the elder sun, it is also life-threatening to treat heart disease, with 290 million people in China, and about 1 billion people worldwide suffering from high blood pressure could develop cardiovascular disease. Cardiovascular disease, the “number one killer” of human health, kills about 20 million people each year, of which about 7 million are due to myocardial infarction.
That’s why people with heart disease long to be cured, and those who don’t want to be caught up in the disease.
The good news is that the possibility of a cure and prevention of heart disease has been validated by a U.S. start-up biotech company called Verve Therapeutics. Verve is looking to use gene editing to deal with heart disease “once and for all.”
This is not the night. In fact, several studies have confirmed that humans’ PCSK9 and ANGPTL3 genes affect the regulation of cholesterol levels in the body. The increase in LDL (LOW DENSITy lipoprotein) cholesterol and triglycerides in the body is an important culprit for diseases such as atherosclerosis, cardiovascular disease, stroke, etc. – these bad cholesterol accumulates in blood vessels, eventually making it difficult for blood to flow into the heart, with the result that high blood pressure and heart oxygen supply are difficult.
Vascular swasheans blocked by bad cholesterol
Verve’s gene-editing therapy is to find ways to turn off both genes and lower the amount of bad cholesterol in the blood, thereby curing and preventing heart disease. With this technology, Verve has received two rounds of investments totalling more than $120m in more than two years of existence, led by GV, formerly known as Google Ventures.
Today, the therapy has made progress in animal experiments. Verve co-founder and CEO Sekar Kathiresan announced at the International Stem Cell Research Association that in the two weeks after intravenous injections of gene editing tools were given to 14 monkeys, LDL cholesterol and triglycerides in the monkeys fell by 59% and 64%, respectively, compared with statins commonly used in heart disease patients.
Notably, this is the first time that gene-editing therapy to prevent and treat heart disease has been successfully tested in primates.
“In principle, Verve’s approach might be better because it’s a one-off treatment,” says Jennifer Doudna, known as CRISPR (simply called Gene Scissors).
This seems to mean that heart disease, the main killer of human health, will be permanently eliminated, the “pot” will be broken, and prevention will no longer be a dream.
Possibilities of “once and for all”
The power of gene editing we’ve heard of, but humans are clearly far from fully aware of it. Verve’s heart disease gene-editing therapy has once again stretched the boundaries of this powerful tool.
What is the principle of this therapy? In fact, as early as 1961, studies showed a link between cholesterol levels and heart disease. So the most important thing to treat heart disease has always been to lower the level of bad cholesterol in the patient.
Since 2003, scientists have found that cholesterol levels in the body are linked to two genes, PCSK9 and ANGPTL3.
PCSK9 is a gene that controls the secretion of cholesterol metabolism enzymes. Several studies have shown that people with high cholesterol-related diseases have strong gene expression in the body and have a functional lysatary mutation, while people with the gene’s dysfunction have lower cholesterol levels, with an average reduction of 28% of LDL cholesterol, and a significantly lower incidence of cardiovascular disease, with an 88% reduction in risk.
When ANGPTL3 failed, the body’s blood levels of triglycerides were also low and the risk of heart attack was reduced by 34 percent.
You know, heart disease usually doesn’t occur until decades after high cholesterol levels; by the age of 50, the most likely right person to have a heart attack has accumulated a lot of plaque in the arteries.
This means that rather than waiting for the cholesterol build-up in the blood vessels to persist and do the hard scavenger work, it is better to suppress cholesterol synthesis at the source.
That’s why pharmaceutical giant Amgent has spent more than 10 years bringing the targeted drug Iloyu monotore, which inhibits the expression of PCSK9, to market. Five years of clinical data showed that the drug could further reduce LDL cholesterol levels by 59% on statins and reduce the risk of cardiovascular disease by 15%.
However, PCSK9 inhibitors need to be injected every few weeks, and the cost of about $450 per month is not affordable for everyone. As a parity, the side effects of long-term statins do afflict many patients, such as abnormal liver function, joint pain, affecting the gastrointestinal system, etc.
Verve’s ambitions are great compared to those of other pharmaceutical companies. Kathiresan hopes that genetic editing will allow humans to acquire natural PCSK9 and ANGPTL3 functionally absent-functional mutations, leading to permanent treatment and prevention of heart disease.
“Our therapy will permanently shut down genes, and cholesterol control will last a long time.” In this way, it can not only reduce the cost of treatment, but also improve the efficiency of treatment, reduce the suffering of patients.
Verve, which was founded just two years ago, was a leading scientific adviser and geneticist at the University of Pennsylvania, Kiran Musunru, and his team had been doing basic research in the field for 15 years. In 2014, Musunru had been able to edit the PCSK9 gene in mice, successfully reducing cholesterol in mice by 35% to 40%.
As with Verve’s latest monkey trial, it all requires only one injection.
Verve’s researchers wrap mRNAs with “edit ingenal instructions” and “guides” in lipid nanoparticles that can quickly transport editing tools to the liver, where both PCSK9 and ANGPTL3 express cholesterol. After intravenous injection, the particle can enter the liver directly and can be quickly absorbed by liver cells, and under the influence of the guide RNA, mRNA can quickly find the target gene in more than 3 billion base pairs and shut it down.
Gene editing process indication
At the same time, compared with the previous gene editing of the virus as a delivery vector, lipid nanoparticles in the body stay time of about 48 hours, far less than the virus system for several months, can reduce the risk of non-target sending.
The first most intuitive result of the trial in the monkeys was that the level sofs of PCSK9 protein in the monkeys’ blood dropped by 89% after one shot and the ANGPTL3 protein levels dropped by 95% – the equivalent of 90% of the two genes being turned off, and the therapy was more efficient.
Two weeks later, ldL cholesterol and triglycerides in monkeys fell by 59% and 64%, respectively. The results “look good compared to statins,” said Joseph Wu, a cardiovascular disease specialist at Stanford University.
How far is it from us?
However, although the possibility of gene-editing therapy for heart disease has been initially proven in primates, scientists are concerned.
Joseph Wu, for example, suspects that only a few weeks of trials will not show the long-term effects of gene editing on patients, after all, gene editing technology is likely to have made changes to genes outside the target without comment, and that current applications have been mixed.
On the one hand, gene editing may indeed be used to block certain terrible genetic diseases and birth defects, such as alcochemy, haemophilia, etc. But it is not clear whether this technology will lead to new diseases in the early stages of development. Especially when treating a common disease such as heart disease, a small side effect can affect a large number of patients.
Indeed, the Verve team did not examine whether other genomes in the monkeys’ liver cells were also “attacked.” Verve’s claim is that no serious adverse reactions have been observed in monkeys, and there is no evidence of “off-target” when editing tools are used in human liver cells grown in laboratory dishes.
Another problem is how long the effects of the technology on cholesterol and triglyceride levels will last, and clinical trials are needed to verify it.
That’s why Jennifer Doudna says it’s “too early to say whether it’s safe and durable.”
Kathiresan, however, is confident. According to its account, the Verve team has identified six other genes similar to PCSK9 and ANGPTL3 that can be used as targets for heart disease. This year, they will select one or more of the top priorities from these potential gene therapies, and expect to start clinical trials by 2023.
This point in time is not far from what Musunru estimated in 2014 when it published the PCSK9 gene editing results in mice that “this method of treating heart disease, from laboratory to human clinical trials, may take about 10 years.”
In terms of the timing of previous drug approvals, if all goes well, we may be at least 8 to 10 years away from the ongoing market of the treatment.
Established 2 years, raising 120 million knives
Verve products have a broad market outlook due to the large global base of people suffering from heart disease.
According to Evaluate Med Tech, the global cardiovascular disease drug market reached $100 billion in 2015. As the prevalence rate increases, so does the size of this market.
Even if Verve is going to have a “one-off” business that can’t match sales of heart medications that need to be taken for a long time, its price selling is certainly much more expensive than the annual use of common drugs, and its share in the market will rise quickly.
Clearly, a range of investors are also excited about Verve’s prospects.
In May 2019, Verve, which has only been in existence for a year, received the first round of $58.5 million in financing, led by GV, ARCH Venture Partners, F-Prime Capital Partners, Biomatics Capital Partners, and VC companies investing in well-known projects around the world, such as China’s Hualu Pharmaceuticals and Shulan Medical.
In just the past Six months, GV has again taken the lead in Filling Verve. Along with Wellington Management and Casdin Capital, Verve received another $63 million.
“Over the past year, Verve has made significant progress on preclinical projects. This could be the cure for the world’s leading cause of death, similar to the history of the polio vaccine that changed history in the last century. Krishna Yeshtock, managing partner of GV, explains why Verve is added in succession.