Scientists are making progress to create a one-time therapy that would permanently lower LDL cholesterol to prevent heart attacks caused by high LDL.
“One is that there are some people that are naturally resistant to heart attack and have lifelong, low levels of LDL,” the cardiologist says. “Second, there are some genes that can be switched off that lead to very low LDL cholesterol, and individuals with those genes switched off are resistant to heart attacks.”
Kathiresan and his team formed a hypothesis in 2016 that if they could develop a medicine that mimics the natural protection that some people enjoy, then they might identify a powerful new way to treat and ultimately prevent heart attacks. They launched Verve in 2018 with the goal of creating a one-time therapy that would permanently lower LDL and eliminate heart attacks caused by high LDL.
"Imagine a future where somebody gets a one-time treatment at the time of their heart attack or before as a preventive measure," says Kathiresan.
The medication is targeted specifically for patients who have a genetic form of high cholesterol known as heterozygous familial hypercholesterolemia, or FH, caused by expression of a gene called PCSK9. Verve also plans to develop a program to silence a gene called ANGPTL3 for patients with FH and possibly those with or at risk of atherosclerotic cardiovascular disease.
FH causes cholesterol to be high from birth, reaching levels of 200 to 300 milligrams per deciliter. Suggested normal levels are around 100 to 129 mg/dl, and anything above 130 mg/dl is considered high. Patients with cardiovascular disease usually are asked to aim for under 70 mg/dl, but many still have unacceptably high LDL despite taking oral medications such as statins. They are more likely to have heart attacks in their 30s, 40s and 50s, and require lifelong LDL control.
The goal for drug treatments for high LDL, Kathiresan says, is to reduce LDL as low as possible for as long as possible. Physicians and researchers also know that a sizeable portion of these patients eventually start to lose their commitment to taking their statins and other LDL-controlling medications regularly.
“If you ask 100 patients one year after their heart attack what fraction are still taking their cholesterol-lowering medications, it’s less than half,” says Kathiresan. “So imagine a future where somebody gets a one-time treatment at the time of their heart attack or before as a preventive measure. It’s right in front of us, and it’s something that Verve is looking to do.”
In late 2020, Verve completed primate testing with monkeys that had genetically high cholesterol, using a one-time intravenous injection of VERVE-101. It reduced the monkeys’ LDL by 60 percent and, 18 months later, remains at that level. Kathiresan expects the LDL to stay low for the rest of their lives.
Verve’s gene editing medication is packaged in a lipid nanoparticle to serve as the delivery mechanism into the liver when infused intravenously. The drug is absorbed and makes its way into the nucleus of the liver cells.
Verve’s program targeting PCSK9 uses precise, single base, pair base editing, Kathiresan says, meaning it doesn't cut DNA like CRISPR gene editing systems do. Instead, it changes one base, or letter, in the genome to a different one without affecting the letters around it. Comparing it to a pencil and eraser, he explains that the medication erases out a letter A and makes it a letter G in the A, C, G and T code in DNA.
“We need to continue to advance our approach and tools to make sure that we have the absolute maximum ability to detect off-target effects,” says Euan Ashley, professor of medicine and genetics at Stanford University.
By making that simple change from A to G, the medication switches off the PCSK9 gene, automatically lowering LDL cholesterol.
“Once the DNA change is made, all the cells in the liver will have that single A to G change made,” Kathiresan says. “Then the liver cells divide and give rise to future liver cells, but every time the cell divides that change, the new G is carried forward.”
Additionally, Verve is pursuing its second gene editing program to eliminate ANGPTL3, a gene that raises both LDL and blood triglycerides. In 2010, Kathiresan's research team learned that people who had that gene completely switched off had LDL and triglyceride levels of about 20 and were very healthy with no heart attacks. The goal of Verve’s medication will be to switch off that gene, too, as an option for additional LDL or triglyceride lowering.
“Success with our first drug, VERVE-101, will give us more confidence to move forward with our second drug,” Kathiresan says. “And it opens up this general idea of making [genomic] spelling changes in the liver to treat other diseases.”
The approach is less ethically concerning than other gene editing technologies because it applies somatic editing that affects only the individual patient, whereas germline editing in the patient’s sperm or egg, or in an embryo, gets passed on to children. Additionally, gene editing therapies receive the same comprehensive amount of testing for side effects as any other medicine.
“We need to continue to advance our approach and tools to make sure that we have the absolute maximum ability to detect off-target effects,” says Euan Ashley, professor of medicine and genetics at Stanford University and founding director of its Center for Inherited Cardiovascular Disease. Ashley and his colleagues at Stanford’s Clinical Genomics Program and beyond are increasingly excited about the promise of gene editing.
“We can offer precision diagnostics, so increasingly we’re able to define the disease at a much deeper level using molecular tools and sequencing,” he continues. “We also have this immense power of reading the genome, but we’re really on the verge of taking advantage of the power that we now have to potentially correct some of the variants that we find on a genome that contribute to disease.”
He adds that while the gene editing medicines in development to correct genomes are ahead of the delivery mechanisms needed to get them into the body, particularly the heart and brain, he’s optimistic that those aren’t too far behind.
“It will probably take a few more years before those next generation tools start to get into clinical trials,” says Ashley, whose book, The Genome Odyssey, was published last year. “The medications might be the sexier part of the research, but if you can’t get it into the right place at the right time in the right dose and not get it to the places you don’t want it to go, then that tool is not of much use.”
Medical experts consider knocking out the PCSK9 gene in patients with the fairly common genetic disorder of familial hypercholesterolemia – roughly one in 250 people – a potentially safe approach to gene editing and an effective means of significantly lowering their LDL cholesterol.
Nurse Erin McGlennon has an Implantable Cardioverter Defibrillator and takes medications, but she is also hopeful that a gene editing medication will be developed in the near future.
Erin McGlennon
Mary McGowan, MD, chief medical officer for The Family Heart Foundation in Pasadena, CA, sees the tremendous potential for VERVE-101 and believes patients should be encouraged by the fact that this kind of research is occurring and how much Verve has accomplished in a relatively short time. However, she offers one caveat, since even a 60 percent reduction in LDL won’t completely eliminate the need to reduce the remaining amount of LDL.
“This technology is very exciting,” she said, “but we want to stress to our patients with familial hypercholesterolemia that we know from our published research that most people require several therapies to get their LDL down., whether that be in primary prevention less than 100 mg/dl or secondary prevention less than 70 mg/dl, So Verve’s medication would be an add-on therapy for most patients.”
Dr. Kathiresan concurs: “We expect our medicine to lower LDL cholesterol by about 60 percent and that our patients will be on background oral medications, including statins that lower LDL cholesterol.”
Several leading research centers are investigating gene editing treatments for other types of cardiovascular diseases. Elizabeth McNally, Elizabeth Ward Professor and Director at the Center for Genetic Medicine at Northwestern University’s Feinberg School of Medicine, pursues advanced genetic correction in neuromuscular diseases such as Duchenne muscular dystrophy and spinal muscular atrophy. A cardiologist, she and her colleagues know these diseases frequently have cardiac complications.
“Even though the field is driven by neuromuscular specialists, it’s the first therapies in patients with neuromuscular diseases that are also expected to make genetic corrections in the heart,” she says. “It’s almost like an afterthought that we’re potentially fixing the heart, too.”
Another limitation McGowan sees is that too many healthcare providers are not yet familiar with how to test patients to determine whether or not they carry genetic mutations that need to be corrected. “We need to get more genetic testing done,” she says. “For example, that’s the case with hypertrophic cardiomyopathy, where a lot of the people who probably carry that diagnosis and have never been genetically identified at a time when genetic testing has never been easier.”
One patient who has been diagnosed with hypertrophic cardiomyopathy also happens to be a nurse working in research at Genentech Pharmaceutical, now a member of the Roche Group, in South San Francisco. To treat the disease, Erin McGlennon, RN, has an Implantable Cardioverter Defibrillator and takes medications, but she is also hopeful that a gene editing medication will be developed in the near future.
“With my condition, the septum muscles are just growing thicker, so I’m on medicine to keep my heart from having dangerous rhythms,” says McGlennon of the disease that carries a low risk of sudden cardiac death. “So, the possibility of having a treatment option that can significantly improve my day-to-day functioning would be a major breakthrough.”
McGlennon has some control over cardiovascular destiny through at least one currently available technology: in vitro fertilization. She’s going through it to ensure that her children won't express the gene for hypertrophic cardiomyopathy.
A company is looking to improve medicines by making them in the nearly weightless environment of space.
Microgravity research could potentially lead to many more discoveries like this one, or even the development of brand-new drugs, but ISS astronauts only have so much time for commercial experiments.
“There are many high-performance products that are only possible to make in zero-gravity, which is a manufacturing capability that cannot be replicated in any factory on Earth.”-- Will Bruey.
The only options for accessing microgravity (or free fall) outside of orbit, meanwhile, are parabolic airplane flights and drop towers, and those are only useful for experiments that require less than a minute in microgravity — Merck’s ISS experiment took 18 days.
The idea: In 2021, California startup Varda Space Industries announced its intention to build the world’s first space factory, to manufacture not only pharmaceuticals but other products that could benefit from being made in microgravity, such as semiconductors and fiber optic cables.
This factory would consist of a commercial satellite platform attached to two Varda-made modules. One module would contain equipment capable of autonomously manufacturing a product. The other would be a reentry capsule to bring the finished goods back to Earth.
“There are many high-performance products that are only possible to make in zero-gravity, which is a manufacturing capability that cannot be replicated in any factory on Earth,” said CEO Will Bruey, who’d previously developed and flown spacecraft for SpaceX.
“We have a team stacked with aerospace talent in the prime of their careers, focused on getting working hardware to orbit as quickly as possible,” he continued.
“[Pharmaceuticals] are the most valuable chemicals per unit mass. And they also have a large market on Earth.” -- Will Bruey, CEO of Varda Space.
What’s new? At the time, Varda said it planned to launch its first space factory in 2023, and, in what feels like a first for a space startup, it has actually hit that ambitious launch schedule.
“We have ACQUISITION OF SIGNAL,” the startup tweeted soon after the Falcon 9 launch on June 12. “The world’s first space factory’s solar panels have found the sun and it’s beginning to de-tumble.”
During the satellite’s first week in space, Varda will focus on testing its systems to make sure everything works as hoped. The second week will be dedicated to heating and cooling the old HIV-AIDS drug ritonavir repeatedly to study how its particles crystalize in microgravity.
After about a month in space, Varda will attempt to bring its first space factory back to Earth, sending it through the atmosphere at hypersonic speeds and then using a parachute system to safely land at the Department of Defense’s Utah Test and Training Range.
Looking ahead: Ultimately, Varda’s space factories could end up serving dual purposes as manufacturing facilities and hypersonic testbeds — the Air Force has already awarded the startup a contract to use its next reentry capsule to test hardware for hypersonic missiles.
But as for manufacturing other types of goods, Varda plans to stick with drugs for now.
“[Pharmaceuticals] are the most valuable chemicals per unit mass,” Bruey told CNN. “And they also have a large market on Earth.”
“You’re not going to see Varda do anything other than pharmaceuticals for the next minimum of six, seven years,” added Delian Asparouhov, Varda’s co-founder and president.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
Centenarians essentially won the genetic lottery, says Nir Barzilai of Albert Einstein College of Medicine. He is studying their genes to see how the rest of us can benefit from understanding how they work.
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Centenarians may have essentially won the genetic lottery, but that doesn’t mean the rest of us are predestined to have a specific lifespan and health span, or the amount of time spent living productively and enjoyably. “Aging is a mother of all diseases,” Dr. Barzilai told me. And as a disease, it can be targeted by therapeutics. Dr. Barzilai’s team is already running clinical trials on such therapeutics — and the results are promising.
More about Dr. Barzilai: He is scientific director of AFAR, American Federation for Aging Research. As part of his work, Dr. Barzilai studies families of centenarians and their genetics to learn how the rest of us can learn and benefit from their super-aging. He also organizing a clinical trial to test a specific drug that may slow aging.
Show Links
Age Later: Health Span, Life Span, and the New Science of Longevity https://www.amazon.com/Age-Later-Healthiest-Sharpest-Centenarians/dp/1250230853
American Federation for Aging Research https://www.afar.org
https://www.afar.org/nir-barzilai
https://www.einsteinmed.edu/faculty/484/nir-barzilai/
Metformin as a Tool to Target Aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
Benefits of Metformin in Attenuating the Hallmarks of Aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/
The Longevity Genes Project https://www.einsteinmed.edu/centers/aging/longevity-genes-project/
