Scientists are making progress to create a one-time therapy that would permanently lower LDL cholesterol to prevent heart attacks caused by high LDL.
Later this year, Verve Therapeutics of Cambridge, Ma., will initiate Phase 1 clinical trials to test VERVE-101, a new medication that, if successful, will employ gene editing to significantly reduce low-density lipoprotein cholesterol, or LDL.
LDL is sometimes referred to as the “bad” cholesterol because it collects in the walls of blood vessels, and high levels can increase chances of a heart attack, cardiovascular disease or stroke. There are approximately 600,000 heart attacks per year due to blood cholesterol damage in the United States, and heart disease is the number one cause of death in the world. According to the CDC, a 10 percent decrease in total blood cholesterol levels can reduce the incidence of heart disease by as much as 30 percent.
Verve’s Founder and CEO, Sekar Kathiresan, spent two decades studying the genetic basis for heart attacks while serving as a professor of medicine at Harvard Medical School. His research led to two critical insights.
“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 new book by Pulitzer-winning physician-scientist Siddhartha Mukherjee will be released from Simon & Schuster on October 25, 2022.
The Song of the Cell begins with the discovery of cells and of germ theory, featuring characters such as Louis Pasteur and Robert Koch, who brought the cell “into intimate contact with pathology and medicine.” This intercourse would transform biomedicine, leading to the insight that we can treat disease by thinking at the cellular level. The slightest rearrangement of sick cells might be the path toward alleviating suffering for the organism: eroding the cell walls of a bacterium while sparing our human cells; inventing a medium that coaxes sperm and egg to dance into cellular union for in vitro fertilization (IVF); designing molecular missiles that home to the receptors decorating the exterior of cancer cells; teaching adult skin cells to remember their embryonic state for regenerative medicines.
Mukherjee uses the bulk of the book to elucidate key cell types in the human body, along with their “connective relationships” that enable key organs and organ systems to function. This includes the immune system, the heart, the brain, and so on. Mukherjee’s distinctive style features compelling anecdotes and human stories that animate the scientific (and unscientific) processes that have led to our current state of understanding. In his chapter on neurons and the brain, for example, he integrates Santiago Ramon y Cajal’s meticulous black ink sketches of neurons into Mukherjee’s own personal encounter with clinical depression. In one lucid section, he interviews Dr. Helen Mayberg, a pioneering neurologist who takes seriously the descriptive power of her patients’ metaphors, as they suffer from “caves,” “holes,” “voids,” and “force fields” that render their lives gray. Dr. Mayberg aims to stimulate patients’ neuronal cells in a manner that brings back the color.
Beyond exposing the insight and inventiveness that has arisen out of cell-based thinking, it seems that Mukherjee’s bigger project is an epistemological one. The early chapters of The Song of the Cell continually hint at the potential for redefining the basic unit of biology as the cell rather than the gene. The choice to center biomedicine around cells is, above all, a conspicuous choice not to center it around genes (the subject of Mukherjee’s previous book, The Gene), because genes dominate popular science communication.
This choice of cells over genes is most welcome. Cells are alive. Genes are not. Letters—such as the As, Cs, Gs, and Ts that represent the nucleotides of DNA, which make up our genes—must be synthesized into a word or poem or song that offers a glimpse into deeper truths. A key idea embedded in this thinking is that of emergence. Whether in ancient myth or modern art, creation tends to be an emergent process, not a linearly coded script. The cell is our current best guess for the basic unit of life’s emergence, turning a finite set of chemical building blocks—nucleic acids, proteins, sugars, fats—into a replicative, evolving system for fighting stasis and entropy. The cell’s song is one for our times, for it is the song of biology’s emergence out of chemistry and physics, into the “frenetically active process” of homeostasis.
Re-centering our view of biology has practical consequences, too, for how we think about diagnosing and treating disease, and for inventing new medicines. Centering cells presents a challenge: which type of cell to place at the center? Rather than default to the apparent simplicity of DNA as a symbol because it represents the one master code for life, the tension in defining the diversity of cells—a mapping process still far from complete in cutting-edge biology laboratories—can help to create a more thoughtful library of cellular metaphors to shape both the practice and communication of biology.
Further, effective problem solving is often about operating at the right level, or the right scale. The cell feels like appropriate level at which to interrogate many of the diseases that ail us, because the senses that guide our own perceptions of sickness and health—the smoldering pain of inflammation, the tunnel vision of a migraine, the dizziness of a fluttering heart—are emergent.
This, unfortunately, is sort of where Mukherjee leaves the reader, under-exploring the consequences of a biology of emergence. Many practical and profound questions have to do with the ways that each scale of life feeds back on the others. In a tome on Cells and “the future human” I wished that Mukherjee had created more space for seeking the ways that cells will shape and be shaped by the future, of humanity and otherwise.
We are entering a phase of real-world bioengineering that features the modularization of cellular parts within cells, of cells within organs, of organs within bodies, and of bodies within ecosystems. In this reality, we would be unwise to assume that any whole is the mere sum of its parts.
For example, when discussing the regenerative power of pluripotent stem cells, Mukherjee raises the philosophical thought experiment of the Delphic boat, also known as the Ship of Theseus. The boat is made of many pieces of wood, each of which is replaced for repairs over the years, with the boat’s structure unchanged. Eventually none of the boat’s original wood remains: Is it the same boat?
Mukherjee raises the Delphic boat in one paragraph at the end of the chapter on stem cells, as a metaphor related to the possibility of stem cell-enabled regeneration in perpetuity. He does not follow any of the threads of potential answers. Given the current state of cellular engineering, about which Mukherjee is a world expert from his work as a physician-scientist, this book could have used an entire section dedicated to probing this question and, importantly, the ways this thought experiment falls apart.
We are entering a phase of real-world bioengineering that features the modularization of cellular parts within cells, of cells within organs, of organs within bodies, and of bodies within ecosystems. In this reality, we would be unwise to assume that any whole is the mere sum of its parts. Wholeness at any one of these scales of life—organelle, cell, organ, body, ecosystem—is what is at stake if we allow biological reductionism to assume away the relation between those scales.
In other words, Mukherjee succeeds in providing a masterful and compelling narrative of the lives of many of the cells that emerge to enliven us. Like his previous books, it is a worthwhile read for anyone curious about the role of cells in disease and in health. And yet, he fails to offer the broader context of The Song of the Cell.
As leading agronomist and essayist Wes Jackson has written, “The sequence of amino acids that is at home in the human cell, when produced inside the bacterial cell, does not fold quite right. Something about the E. coli internal environment affects the tertiary structure of the protein and makes it inactive. The whole in this case, the E. coli cell, affects the part—the newly made protein. Where is the priority of part now?” [1]
Beyond the ways that different kingdoms of life translate the same genetic code, the practical situation for humanity today relates to the ways that the different disciplines of modern life use values and culture to influence our genes, cells, bodies, and environment. It may be that humans will soon become a bit like the Delphic boat, infused with the buzz of fresh cells to repopulate different niches within our bodies, for healthier, longer lives. But in biology, as in writing, a mixed metaphor can cause something of a cacophony. For we are not boats with parts to be replaced piecemeal. And nor are whales, nor alpine forests, nor topsoil. Life isn’t a sum of parts, and neither is a song that rings true.
[1] Wes Jackson, "Visions and Assumptions," in Nature as Measure (p. 52-53).