New Gene-Editing Therapy Could Combat High Cholesterol

A report from a Massachusetts–based biotech company, Verve Therapeutics, showed gene editing can reduce cholesterol levels noticeably in patients, and that too safely. The company shared the results of the experimental cholesterol-lowering treatment that used gene editing at a meeting of the American Heart Association. 

This was part of an experiment where a handful of patients with severe heart disease causing them chest pain and heart attacks volunteered for a treatment that used gene editing after cholesterol-lowering medications failed to bring down their cholesterol as low as recommended by cardiologists.

Cholesterol is a waxy substance that's found in the cells of your blood. It is needed by your body in order to build healthy cells and make vitamin D and hormones. However, high levels of cholesterol in your blood develop fatty deposits in your blood vessels. This narrows or blocks your arteries, increasing your risk of heart disease or a stroke, two leading causes of death in the US.

According to the Centers for Disease Control and Prevention (CDC), almost 2 in 5 adults in the US have high cholesterol.

Given the severity of the situation, scientists and researchers have been leveraging new technologies to treat this problem. Besides lifestyle modifications in terms of healthy diet and regular exercise, the traditional approaches to lowering cholesterol levels include medications like statins, ezetimibe, and PCSK9 inhibitors. 

In recent years, gene editing technologies have been showing promise in addressing genetic factors that contribute to high cholesterol levels, as happened in this experiment, which has been unlike anything tried in patients before.

Gene editing or genome editing is about changing the DNA of organisms like plants, animals, and bacteria. These technologies allow scientists to add, remove, or alter genetic material at a particular spot in the genome. Scientists are using genome editing to investigate diseases affecting humans and develop treatments to prevent and treat them.

While it was many decades ago that genome editing technologies were initially developed, it wasn't until recent years that CRISPR emerged as the popular technique to edit DNA. Due to this new genome editing tool being cheaper, simpler, faster, more efficient, and more accurate than other methods, many scientists now use the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technique.

Click here for the list of the top five CRISPR companies to invest in.

Gene Editing Treatment Cuts Down Cholesterol

Now, in the latest experiment, Verve Therapeutics had ten patients join the trial in New Zealand and the UK. These patients had an average age of 54 and a genetic abnormality called familial hypercholesterolemia (FH) that affects around one million people in the US. 

Led by Verve's chief executive, Dr. Sekar Kathiresan, in this new study, patients got microscopic lipid nanoparticles' single infusion, which contained a molecular factory within them. This molecular factory is to edit a specific gene in the liver, the place of cholesterol synthesis. 

This gene is PCSK9, which is responsible for raising the bad kind of cholesterol, i.e., LDL (low-density lipoprotein) cholesterol. The treatment used a novel and more precise form of CRISPR called base editing to inactivate PCSK9.

In this experiment, the idea was to block this PCSK9 gene by carrying the lipid nanoparticles directly to the liver through the blood. When they enter liver cells and open up to reveal two molecules, one directs the DNA to make a gene editing tool while the other one is a guide that takes this tool to the PCSK9 gene that requires editing.

Seen by many as “almost like science fiction,” the single cholesterol-lowering treatment turns off the PCSK9 gene for lifelong protection from heart disease. According to Verve, this is the “first-ever evidence” of rewriting a single DNA letter in the human liver and having a clinical effect. 

“It is a breakthrough to have shown in humans that in vivo base editing works efficiently in the liver.”

– Gerald Schwank, a gene editing researcher at the University of Zurich (not involved in the clinical trial)

Under the small trial, patients didn't receive the same dose, rather of varying levels. Those who received lower doses didn't see much results. However, three patients who received the highest doses had their LDL levels drop significantly. The highest dose saw a reduction of 55%, and the next-highest dose had a 39% and 48% reduction.

“This is a strategy that could be revolutionary. But we have to make sure it's safe.”

– Karol Watson, a cardiologist at UCLA

If we take a look at those who received the higher doses, the study shows they had flu-like symptoms for a few hours. Among these, two patients had serious adverse events; one patient suffered a cardiac arrest just over a month after getting the infusion, while the other patient had a heart attack the day after the infusion. It was shown post-mortem that the former one had many of his coronary arteries blocked while the latter experienced chest pains but didn't report it. The independent data safety and monitoring board of the trial considered these events the result of the patient's underlying severe heart disease and decided to keep the study going.

The company plans to enroll more patients in its study next year and have a larger trial starting in 2025. Late last year, the US Food and Drug Administration (FDA) paused the trial's start only to lift it this year, allowing Verve Therapeutics to begin enrolling patients in the US as well. The US regulator gave the green light after the company shared insights and data regarding gene editing not altering DNA in sperm and egg cells. 

The Promising Future of Gene Editing in Preventive Cardiology

A decade ago, when researchers began studying the problem, they discovered rare but healthy individuals with impossibly low cholesterol levels due to the mutated and non-functioning PCSK9 gene, resulting in those people being protected from heart disease. This led to the creation of antibodies to block PCSK9 that patients injected themselves with once a week. Over the years, the development led to RNA injections that were taken twice yearly to prevent the gene from being made.

The thing is, even after being diagnosed with heart disease, less than 60% of patients take a statin, and only one-fourth take one of the more effective, high-intensity statins. Currently, the care involves taking daily pills and intermittent injections for decades, placing a heavy burden on not just patients but also providers and the health care system, noted Andrew Bellinger, chief scientific officer of Verve Therapeutics. Hence, there is interest and focus on gene editing as a single treatment and a lifetime response. 

A study in early 2018 from the Perelman School of Medicine at the University of Pennsylvania found that using base editing, we can mimic the protective effects of a genetic mutation — loss of function in the gene for ANGPTL3, that lowers cholesterol levels and heart disease risks. 

According to cardiologists and gene editing experts, these treatments have the potential to transform preventive cardiology.

“Even for seasoned veterans of this field like myself, this is a day we will look back on. I see today as crossing a Rubicon in a good way. This is not a small step. It is a leap into new territory.”

– Fyodor D. Urnov, a gene editor at the Innovative Genomics Institute in Berkeley, California

The findings of this experiment could be really beneficial for millions of patients around the world who are grappling with heart disease, which remains a leading cause of death. In the US alone, we see over 800,000 people having heart attacks every year.

The promising data from the trial and the potential of the treatment led the pharmaceutical giant Eli Lilly to make a contribution of $60 million to collaborate with Verve Therapeutics. But this is not all. The company also chose to acquire additional rights to Verve's programs for an additional $250 million. 

Eli Lilly's chief scientific and medical officer, Dr. Daniel Skovronsky, stated in an interview that up until now, gene editing was seen as a treatment that should only be reserved for “very rare diseases where there is no other treatment.” But it can now be used for more common diseases, provided this technique can be made “safe and widely available.”

This treatment can be extremely beneficial for younger people, specifically with genetically high cholesterol levels and very high lifetime risks. Early gene editing in younger patients may prevent arteries from hardening. “It could be an incredible medicine,” said Dr. Martha Gulati, director of preventive cardiology at the Smidt Heart Institute of Cedars-Sinai Medical Center in Los Angeles. She was not involved in the trial and is the president of the American Society for Preventive Cardiology. However, this is well into the future as it still needs to be seen if gene editing is safe, successful, and has lasting effects.

So, while exciting, safety remains the primary concern, with experts talking about the off-target effects of the treatment, which involves unintended editing of genes that could potentially cause health problems such as cancer, hence presenting a lot of uncertainties here. However, according to the company, they didn't detect any off-target editing in human liver cells, and the risk is very low. 

The first patient was treated only six months ago, though a previous study in monkeys lasted two and a half years, lowered bad cholesterol up to 69 percent, and showed persistent results. There are also concerns about the treatment cost, given that some approved gene therapies have price tags in the millions. 

Having said that, the results have been pretty impressive and exciting, with the remarkable treatment having the potential to provide a powerful new way to prevent heart attacks and strokes. This is clearly just the beginning, as more trials in a broader range of patients still need to be carried out. 

Click here to learn how promising the gene editing market is likely to be by 2030.

Companies Tackling the Cholesterol Problem via Unique Research-intensive Means

Now, let's take a look at some prominent names that are researching to tackle this grave problem of cholesterol in adults and younger generations with novel means. 

#1. Amgen

The biotechnology company develops and manufactures various human therapeutics and is known for its work in cardiovascular diseases. Back in 2015, the FDA approved Amgen's cholesterol-lowering medication called Repatha Injection that inhibits PCSK9. In 2021, Repatha gained FDA approval to reduce bad cholesterol for pediatric patients with heterozygous familial hypercholesterolemia (HeFH). 

With a market cap of $151.9 billion, AMGN shares are trading at $283.90, up 8% this year. The company posted revenue trailing twelve months (TTM) of $26.833 bln while having EPS (TTM) of 14.07, P/E (TTM) of 20.18, and ROE (TTM) of 133.80%. Amgen also pays a dividend yield of 3.17%.

#2. Regeneron Pharmaceuticals

Regeneron is involved in the development of drugs that target PCSK9 to reduce LDL cholesterol. In 2021, the FDA approved Evkeeza to treat adult and pediatric patients with a rare, inherited form of high cholesterol. Earlier this year, the federal agency approved the expanded use of its drug in children aged 5 to 11 years as well.

With a market cap of $92.55 billion, REGN shares are trading at $849.53, up 17.75% this year. The company posted revenue trailing twelve months (TTM) of $13.097 bln while having EPS (TTM) of 35.05, P/E (TTM) of 24.24 and ROE (TTM) of 17.22%. 

#3. AstraZeneca

The pharmaceutical company, with a focus on cardiovascular and metabolic diseases, revealed last year that its AZD8233 reduced LDL cholesterol levels by 73%. This year, AstraZeneca signed a three-year agreement with Chinese biotech to work on new drugs to target hypercholesterolemia.

With a market cap of $206.14 billion, AZN shares are trading at $67.40, down 1.92% this year. The company posted revenue trailing twelve months (TTM) of $44.99 bln while having EPS (TTM) of 1.89, P/E (TTM) of 35.19, and ROE (TTM) of 16.30%. AstraZeneca also pays a dividend yield of 2.18%.

#4. Pfizer 

The pharmaceutical giant has been involved in research related to cholesterol-lowering drugs and, in 2021, announced topline results from the Phase 2b study of its investigational antisense therapy called vupanorsen for lowering non-high-density lipoprotein cholesterol.

With a market cap of $160.4 billion, PFE shares are trading at $28.50, down 44.56% this year. The company posted revenue trailing twelve months (TTM) of $68.538 bln while having EPS (TTM) of 1.82, P/E (TTM) of 15.6, and ROE (TTM) of 11.05%. Pfizer also pays a dividend yield of 5.91%.

#5. Novartis

This global healthcare company has been involved in research and development in the field of cholesterol management. In August this year, Novartis presented new long-term Leqvio (inclisiran) data that demonstrated its consistent efficacy and safety in reducing LDL cholesterol beyond six years of treatment when used twice a year in addition to statin therapy.

With a market cap of $224.445 billion, NVS shares are trading at $98.87, up 8.63% in 2023. The company posted revenue trailing twelve months (TTM) of $47.885 bln while having EPS (TTM) of 3.59, P/E (TTM) of 27.42, and ROE (TTM) of 14.94%. Novartis also pays a dividend yield of 3.55%.

Other companies working in this sphere are pharmaceutical company Sanofi, biopharmaceutical company Esperion Therapeutics, and Merck & Co., among many more.

Overall, as the scientific community continues to explore the full implications of this breakthrough, the promise of gene editing in medicine becomes increasingly evident.

Click here to learn all about investing in genomics and CRISPR.