A vaccine for heart disease?

Before the age of 48, he would never have imagined that his blood pressure, which had been low for a long time, would suddenly soar to nearly 200.
He had a dull stomachache and was diagnosed with a heart attack.

After that, he ascended the fifth floor easily, pausing every two floors to catch his breath for a long time before continuing his climb.
The daily medicine is endless, blood pressure, fat reduction.
Once in a while, when the pain became severe, he swallowed a quick relief pill and gritted his teeth.

There are 290 million heart patients in China who, like Lao Sun, turn into medicine jars and may be in danger of death at any time.
About 1 billion people worldwide suffer from high blood pressure and may develop cardiovascular disease.
Cardiovascular disease, the number one killer of human health, kills about 20 million people a year, with myocardial infarction accounting for about 7 million.

Because of this, people with heart disease want to be cured, and those who don’t want to be spared the disease.

The good news is that a shot at curing and preventing heart disease has been tested by an American biotech start-up called Verve Therapeutics.
Verve hopes to use gene editing to tackle heart disease “once and for all”.

This is not impossible.
In fact, several studies have shown that two genes, PCSK9 and ANGPTL3, affect cholesterol levels in humans.
Increased levels of LDL (low-density lipoprotein) cholesterol and triglycerides are a major cause of atherosclerosis, cardiovascular disease, stroke and other diseases — the bad cholesterol builds up in the blood vessels, making it difficult for blood to flow to the heart, resulting in high blood pressure and difficulty getting oxygen to the heart.

Blood vessels obstructed by bad cholesterol are shown here
Verve’s proposed gene editing therapy seeks to turn off the two genes and lower bad cholesterol levels in the blood, thereby eradicating and preventing heart disease.
The technology has enabled Verve to raise a total of more than $120 million in two rounds over its two-year history, both led by GV (formerly Google Ventures).

Today, the treatment has advanced in animal trials.
Verve co-founder and CHIEF executive Sekar Kathiresan announced at the International Society for Stem Cell Research that after 14 monkeys were given gene-editing tools intravenally, their LDL cholesterol and triglyceride levels dropped 59 percent and 64 percent, respectively, in the two weeks after the injection, compared with statin drugs commonly used in heart disease patients.

Notably, this is the first time a gene editing therapy to prevent or treat heart disease has been successfully tested in a primate.

“In principle, Verve’s approach might be better, because it’s a one-time treatment,” says Jennifer Doudna, the goddess of CRISPR (or, more simply, gene scissors).

This would seem to mean that the major killer of human health, heart disease, would be permanently eliminated, the medicine would be broken, and prevention would no longer be a dream.

The possibility of “once and for all.

We’ve heard a lot about the power of gene editing, but it’s clear that humans are far from knowing the full picture.
Verve’s research on gene editing therapy for heart disease extends the boundaries of this powerful tool once again.

So how does this work?
In fact, studies dating back to 1961 have linked cholesterol levels in people with a higher risk of heart disease.
So for a long time, the most important thing to do with heart disease was to lower the bad cholesterol in the body.

Since 2003, scientists have linked cholesterol levels to two genes — PCSK9 and ANGPTL3.

PCSK9 is a gene that controls the secretion of enzymes involved in cholesterol metabolism.
Multiple studies have shown that the gene is strongly expressed and functionally acquired in people with high cholesterol related diseases.
People with the deletion-type mutation had lower cholesterol levels, reduced LDL cholesterol by an average of 28 percent, had significantly lower rates of cardiovascular disease, and had an 88 percent lower risk.

PCSK9 gene
When ANGPTL3 fails, blood levels of triglycerides are low, reducing the risk of heart attack by 34 percent.

Heart disease usually takes decades after high cholesterol levels;
By the age of 50, the right-most person at risk for a heart attack had a large accumulation of “plaques” in their arteries.

This means that, rather than waiting for cholesterol to build up in the blood vessels before doing the hard work of scavenging it, it is better to suppress cholesterol synthesis in the first place.

That’s why pharmaceutical giant Amgen has spent more than a decade bringing to market a targeted drug called Iluumab that inhibits PCSK9 expression.
Five years of clinical data showed the drug could reduce LDL cholesterol levels by a further 59 percent over statins and reduce cardiovascular risk by 15 percent.

However, PCSK9 inhibitors require injections every few weeks, and the cost of about $450 a month is not something everyone can afford.
As an affordable alternative, the side effects of long-term statin use, such as liver abnormalities, joint pain and gastrointestinal problems, afflict many patients.

Compared with other drug companies, Verve’s ambitions are enormous.
Kathiresan hopes to make natural PCSK9 and ANGPTL3 function-deficit mutations available to all humans through gene editing, leading to permanent treatment and prevention of heart disease.

“Our treatment will turn off the gene forever, and control cholesterol for a long time and a lifetime.”
So, can reduce treatment cost already, can improve treatment efficiency again, alleviate sufferer pain.

Verve is only two years old, but its chief scientific adviser, Kiran Musunru, a geneticist at the University of Pennsylvania, and his team have been doing basic research in the field for 15 years.
In 2014, Musunru was able to edit the PCSK9 gene in mice, reducing cholesterol by 35 to 40 percent.

As with Verve’s recently completed monkey trials, all it takes is a single injection.

Verve’s researchers wrapped mRNA with “edit instructions” and “guide” Rnas in lipid nanoparticles that whisked the editing tool to the liver, where PCSK9 and ANGPTL3 are expressed to promote cholesterol production.
After intravenous injection, the particle can enter the liver directly and be quickly absorbed by liver cells. With the help of guide RNA, the mRNA can quickly find the target gene in more than 3 billion base pairs and turn it off.

The gene editing process

At the same time, compared with the previous gene editing selection of viruses as delivery vectors, lipid nanoparticles stay in the body for about 48 hours, far less than the virus system’s stay of several months, which can reduce the risk of non-target editing by rashness.

The team’s first and most immediate results in monkeys were an 89 percent drop in PCSK9 protein levels and a 95 percent drop in ANGPTL3 protein levels in the blood after a single shot — the equivalent of turning off the two genes by 90 percent, respectively. The treatment was highly efficient at editing.

After two weeks, the monkeys’ LDL cholesterol and triglyceride levels dropped 59 percent and 64 percent, respectively.
The results “look good compared to statins,” said Joseph Wu, a cardiovascular specialist at Stanford University.

How far is it from us?

But despite preliminary evidence that gene editing therapy could be a treatment for heart disease in primates, scientists are still worried.

Joseph Wu, for example, suspects that a few weeks of testing will not show the long-term effects of gene editing on patients. After all, gene-editing technology is likely to alter genes beyond the target without comment.

On the one hand, gene editing may indeed be used to block some terrible genetic diseases and birth defects, such as albinism and hemophilia.
But at this early stage of development, it is unclear whether the technology will lead to new diseases.
Especially in the treatment of common diseases such as heart disease, a small side effect can affect a large number of patients.

Indeed, Verve’s team did not examine whether other genomes in the monkeys’ liver cells were also being attacked.
Verve said no serious adverse reactions had been observed in monkeys, and that there was no evidence of “off-target” editing tools when used in lab dishes to grow human liver cells.

Another question is how long the technology will have an impact on cholesterol and triglyceride levels, which will need to be tested in clinical trials.

Because of this, “it’s too early to say if it’s safe and durable,” Says Jennifer Doudna.

But Kathiresan is confident.
Verve’s team has identified six other genes similar to PCSK9 and ANGPTL3 that could be targeted for heart disease, he said.
This year, they will select one or more of these potential gene therapies as their top priority and expect to start clinical trials by 2023.

That’s not much different from what Musunru estimated in 2014, when it published the results of PCSK9 gene editing in mice, that it could take a decade or so for such a treatment to move from laboratory to human clinical trials.

Based on past drug approvals, if all goes well, it could be at least eight to 10 years before the treatment is on the market.

Founded 2 years ago, financing $120 million

Due to the large number of people suffering from heart disease around the world, Verve products also have a broad market prospect.

According to Evaluate Med Tech’s calculation, the global market for cardiovascular drugs reached 100 billion US dollars in 2015.
With the gradual increase in the prevalence rate, the size of the market is also growing.

Even if Verve is a “one-off” business and cannot match long-term sales of heart drugs, it will be far more expensive than the annual cost of regular drugs, and its market share will rise quickly.

Clearly, a range of investors are also excited about Verve’s prospects.

In May 2019, Verve, founded only a year ago, received the first round of financing of 58.5 million US dollars. GV led the investment, ARCH Venture Partners, F-Prime Capital Partners and Biomatics Capital Partners followed the investment. The VC Partners with the investment have invested in many well-known projects around the world, such as China’s Hualing Pharmaceutical, And Biomatics Capital Partners.

This past June, the GV again led the charge on Verve.
Adding Wellington Management and Casdin Capital raised an additional $63 million.

“Over the past year, Verve has made significant progress in its preclinical program.
This could be the cure for the world’s leading cause of death in the same way that the polio vaccine changed history in the last century.”
Krishna Yeshtock, GV’s managing partner, explains the continued Verve.

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