2025-12-05 02:06:06
The new gene therapy focuses on a type of DNA error shared by a wide range of rare inherited conditions.
On the surface, cystic fibrosis and Tay-Sachs disease have nothing in common. Although both are inherited genetic disorders, one causes thick mucus buildup in the lungs, making it progressively harder to breathe; the other gradually leads to a buildup of fatty molecules that kills brain cells.
But under the hood, the diseases share a common villain: Nonsense mutations.
Like a molecular “stop sign,” these mutations instruct cells to abandon making certain proteins, resulting in truncated versions that don’t work and lead to disease. Gene-editing tools can correct mutated genes by targeting them one by one for each disease. While this approach can save lives, it takes time and a lot of resources to develop.
Why not aim for the common villain?
This month, a team led by David Liu at Harvard University developed a gene-editing tool to correct nonsense mutations. Called PERT, the tool tackles the mutations head on, allowing cells to ignore the mutations and continue producing proteins to their full length and potential.
In cultured human cells and mice with nonsense mutations, a single dose of PERT rescued protein production and eased disease symptoms. Because PERT is inserted into the genome, the treatment is, in theory, one-and-done.
The gene therapy could be a boon for rare diseases. More than 7,000 inherited diseases affect hundreds of millions of people around the world. Nonsense mutations are involved in roughly 30 million. Few have any treatment or cure.
“The most effective strategy for addressing this unmet need would be to develop therapies that are effective against multiple rare disorders,” wrote Kim Keeling at the University of Alabama, who was not involved in the study.
A more universal gene editor fits the bill. If proven safe and effective in humans, PERT sets the stage for more affordable gene therapies, faster development times, and more importantly—hope for people with rare diseases that have been largely sidelined in the past.
Proteins are the workhorses of our bodies. They’re the foundational building blocks of tissues and organs and are in charge of intricate biological functions, from regulating immune responses to digesting food.
The blueprints for proteins are embedded in our DNA as three-letter codons. Each codon represents a single amino acid, the basic molecules that make up proteins. These codons are transcribed into molecular transports called mRNA, which shuttle the information to the cell’s protein-making factory for assembly.
The factory reads the codons one by one and instructs a team of molecular chauffeurs called tRNA to grab the correct amino acid and bring it to the assembly line. In this way, the factory translates the body’s genetic code into a ribbon-like protein chain.
Nonsense mutations bring the process to a screeching halt. The factory needs instructions on when a protein chain is complete so it can be released for further processing. These instructions are called “stop codons” and are made of several unique genetic letter combinations.
Some genetic diseases have a single genetic mutation that turns a protein-making codon into a stop codon—basically, pulling an emergency switch to shut down production. Rather than making the entire functional protein, the cell destroys mRNA shuttles and truncates the resulting proteins. These proteins are less stable or struggle to perform their roles.
Previous studies found a workaround: Nonsense suppression.
Engineered suppressor tRNA molecules can skip over nonsense mutations. Like molecular smugglers, these synthetic RNA molecules sneak amino acids to spots where the protein should have been terminated. This trick rewires the code and lets the protein-making factory skip the stop command and keep making the rest of the protein.
The strategy has already had successes. In one study, synthetic suppressor tRNA molecules delivered by a virus were shown safe and effective in mice with a nonsense mutation, and beneficial effects from a single treatment lasted for more than half a year. Another suppressor tRNA molecule wrapped up in a fatty bubble for delivery—a commonly used system in gene therapies—restored production of a protein in mice with cystic fibrosis, allowing them to better breathe.
Both methods have downsides though. Viral carriers, even when stripped of their disease-causing traits, can still stir up immune responses. And although using fatty bubbles to deliver therapies is relatively safer, they require multiple doses in chronic genetic diseases.
Liu and colleagues brainstormed a one-and-done therapy that directly inserts instructions for suppressor tRNA molecules into cells or an animal’s genetic code.
After screening thousands of tRNA variants, they found a highly active candidate as a starting point. Using prime editing, a type of small and precise gene editor, they altered natural versions of tRNA into suppressor versions that recognized a specific mutated stop codon.
Rather than terminating the building project, the engineered tRNA shuttled an amino acid into place to override the mutation and finish constructing the full-length protein.
The team tested the new tool, called PERT, in several human cell types in petri dishes. The cells harbored nonsense mutations for different genetic diseases, including cystic fibrosis and Tay-Sachs disease. A single dose increased working proteins by 20 to 70 percent regardless of the disease.
The therapy also worked in mice with a nonsense mutation causing a severe disease called Hurler syndrome in humans. Here, the body struggles to make a protein that degrades a type of sugar molecule, which builds up and causes cellular mayhem. Seven weeks after a single treatment, the mice had 8 percent more of the protein—enough to decrease harmful sugars and alleviate symptoms.
PERT’s strength is in its versatility. In a screen of over 14,000 mutated stop codons, the gene editor bypassed mutations roughly 70 percent of the time.
But while the results are promising, altering nonsense mutations can be fickle.
Inserting an amino acid into a growing protein chain can impact its function and stability. Proteins largely depend on their 3D structures to interact with other biological molecules, and a single change in amino acid makeup could alter the overall architecture.
It’s therefore unlikely “that the engineered tRNA will recover optimal function for all proteins” that have nonsense mutations, wrote Keeling. The current study focused on one stop codon: UGA. Several others exist and are now targets for other suppressor tRNA molecules.
Using prime editing, the molecules can linger in the body to continually produce the engineered versions without need for repeated jabs. From here, scientists must conduct long-term animal studies to test the edited tRNA’s stability and side effects.
There’s also the dosage problem. An optimal amount for liver tissue may be too large or ineffective for the heart or lungs. Eventually the team envisions a library of PERT tools, tailored to each organ and frozen in a fridge for use on command. With their work, the team has brought the therapeutic use of suppressor tRNA molecules “a step closer,” wrote Keeling.
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2025-12-03 05:29:25
Months after the one-and-done treatment, a three-year-old boy with Hunter syndrome is thriving.
Ollie Chu was three years old when he received an infusion that would change his life.
Born with a rare inherited condition called Hunter syndrome, Ollie’s body couldn’t produce an enzyme that breaks down complex sugars.
Just a few months after his birth, the sugars had built up everywhere, wreaking havoc on lungs, liver, skin, and brain. In Hunter syndrome, joints stiffen and airways narrow, making it hard to breathe. The brain also struggles to grow, resulting in developmental delays and cognitive problems. Most kids diagnosed with the condition don’t live past 20.
There are a few treatments. One drug on the market counteracts some bodily symptoms but at a hefty price. It must be taken weekly for life and can’t rescue the brain. Another option is a full bone marrow replacement. While this offers a long-term solution, the procedure is risky for toddlers and depends on the availability of matching donors, who are few and far between.
Ollie’s treatment is new. Roughly a year ago, researchers at the University of Manchester removed stem cells from his body, genetically inserted a functional copy of the gene encoding the missing enzyme, and infused the edited cells back into his body through a catheter.
Now, he no longer depends on weekly drug infusions. “[He] is doing great since having the gene therapy. We have seen dramatic improvements, and he continues to grow physically and cognitively,” said his dad, Ricky, in a press release.
Ollie is one of five very young children in an ongoing clinical trial of gene therapy for Hunter syndrome. Led by the Royal Manchester Children’s Hospital and collaborators, researchers hope the one-and-done therapy will slash treatment time and offer a lasting solution.
“Gene therapy is not only safer and more effective [than bone marrow transplant], but it enables us to use the child’s own cells which cuts out the need to find a donor,” said joint clinical lead Rob Wynn. If successful, the principles could be adapted for other genetic diseases.
Cells are constantly building, destroying, and recycling proteins. They monitor the levels of different molecules—sugars, fats, and proteins—and shuttle excess to the lysosome.
Think of the lysosome as a cell’s “stomach.” Each bubble-like structure contains acidic fluids and a menagerie of enzymes to break down different types of molecules.
One of these enzymes, called iduronate-2-sulfatase (IDS), is missing in Hunter syndrome. The enzyme exists in all cells, but it’s most active in the liver, skin, immune system, and brain. Rather than staying put, IDS loves to roam about and explore neighboring cells. In other words, if only a fraction of cells can make the enzyme, its effects would still spread beyond just the treated ones.
The enzyme replacement therapy Ollie and other kids with Hunter syndrome begin early in life relies on IDS. Here, the enzyme is infused into the bloodstream where it’s absorbed into multiple tissues to help clean out toxic sugars. The treatment improves lung and liver function and helps with joint mobility. But due to its large size, it can’t enter the brain. Hence, the disease continues to attack neural function.
At the root of Hunter syndrome is the gene that produces IDS. Using viruses and gene editing, studies have shown that delivering a healthy version of the gene to mice boosts production of the enzyme. Some genetic diseases have only a single DNA letter change. But the IDS gene mutates in hundreds of ways, making it difficult to engineer a universal gene therapy.
A bone marrow transplant from a matching healthy donor is one workaround. Donor stem cells gradually develop into a range of healthy blood and immune cells. Because they have a normal version of the IDS gene, these cells pump the missing enzyme throughout the body.
A transplant is a one-and-done treatment, but the recipient must take immunosuppressant drugs for the rest of their life, increasing the chance of infections. And the wait for a matching donor can be very long.
In Ollie’s treatment, researchers harvested his own stem cells for gene therapy. Because the cells come from his body, they’re more likely to evade immune rejection.
The approach is based on a mouse study by Brian Bigger and colleagues, who is also co-leading the clinical trial. It uses a viral carrier, stripped of disease-causing genes, to shuttle a healthy IDS gene into blood stem cells outside the body. The edited cells are then infused back into the patient. The virus inserts the gene directly into the cell’s genome, ensuring the replacement isn’t lost when the cells divide.
Rather than using a natural version of IDS, the team added a snippet to the gene that helps the enzyme better tunnel into the brain. Once infused, the edited stem cells multiply into a variety of blood and immune cells that roam the body and release the working enzyme.
In mice modeling Hunter syndrome, a single treatment completely reversed brain symptoms for up to 16 months—or almost their entire lifespan. Other organs also benefited without notable side effects.
In late 2024, Ollie, at just three years of age, underwent a similar procedure. His doctors collected and isolated his blood stem cells and genetically tweaked them to churn out the missing enzyme. As he watched cartoons, the team infused two doses of the edited cells through a catheter. He quickly recovered and was discharged from the hospital a few days later.
Within three months of the infusion, Ollie was able to come off the weekly drug infusions that had dominated his life. His speech and motor abilities improved, allowing him to ride a tricycle, hang out with friends, and enjoy a normal childhood.
“I want to pinch myself every time I tell people that Oliver is making his own enzymes,” his mother Jingru told the BBC. “Every time we talk about it I want to cry because it’s just so amazing.”
The team is recruiting other children with Hunter syndrome in the ongoing clinical trial to further test safety and efficacy. Because symptoms progress so rapidly before causing brain damage, the trial only accepts patients between three and 12 months of age. (At first, doctors thought Ollie was too old, but testing showed his condition had progressed only a little.) Once treated, the children will be followed for two years to gauge the therapy’s effects against common symptoms, such as delayed learning, hearing issues, and heart and lung problems.
If successful, the same gene-editing approach could be used to treat other inherited diseases involving stem cells. Ollie’s parents are hopeful the therapy might be extended to older children, including his five-year-old brother Skyler, who also has Hunter syndrome but is currently too old for the trial.
Still, to his father Ricky, the experimental treatment has been a success.
“We’re excited for Ollie’s future. Seeing the difference for Ollie pre-and post-transplant has made us believers,” he said. “We hope that one day, a treatment becomes available for all children at all stages of Hunter syndrome.”
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2025-12-02 04:52:51
There’s a golden opportunity to avoid mistakes made here on Earth.
Space is getting busier as national space agencies and private companies increase the tempo of launches. But today’s approach to space exploration is unsustainable, say researchers, and we need to do more to make sure the orbital economy is a circular one.
While companies like SpaceX have made progress with reusable rockets, most launch vehicles are used only once, and their remains are left to either burn up in the atmosphere or clutter low-Earth orbit. They also dump huge quantities of greenhouse gases and ozone-depleting chemicals into the upper atmosphere.
Satellites are similarly unsustainable. After completing missions, they’re often either moved to a “graveyard orbit,” or worse, they add to the growing pile of space junk making low-Earth orbit increasingly hard to navigate.
As the pace of launches grows, these approaches are no longer viable, say researchers. In a paper published in Chem Circularity, scientists argue we need to shift to a “circular space economy” designed around the principles of reducing, repairing, and recycling.
“As space activity accelerates, from mega-constellations of satellites to future lunar and Mars missions, we must make sure exploration doesn’t repeat the mistakes made on Earth,” the University of Surrey’s Jin Xuan says in a press release. “A truly sustainable space future starts with technologies, materials, and systems working together.”
Progress already made in shifting industries like electronics and automotive manufacturing to more circular practices could provide a template for the space economy, say the researchers.
To reduce waste in the industry, they say spacecraft need to be more durable to increase their lifespans. This could slash material waste from the vehicles themselves and reduce the number of launches required.
Making spacecraft more repairable could also play an important role, they note. To make this possible, space stations would need to become hubs that carry out maintenance and build spacecraft components. They could also refuel satellites already in orbit to extend their lifespans.
Recycling spacecraft is more challenging due to the enormous amount of wear and tear they undergo in the harsh conditions of space and the punishing process of re-entering the atmosphere. The researchers say companies need to further develop soft-landing systems like parachutes and airbags to ensure vehicles can be brought back safely.
The study also calls for systematic efforts to clear existing orbital debris. These would reduce the risk of collisions but could also recover valuable materials. The work would require new tools like robotic arms and nets that can safely capture spacecraft moving at thousands of miles per hour.
The biggest challenge, the researchers say, is this would represent a fundamental shift in the way the space industry operates. That means piecemeal progress on individual components or processes won’t cut it: What’s needed is a system-wide commitment to radically different ways of operating.
“We need innovation at every level, from materials that can be reused or recycled in orbit and modular spacecraft that can be upgraded instead of discarded, to data systems that track how hardware ages in space,” says Xuan. “But just as importantly, we need international collaboration and policy frameworks to encourage reuse and recovery beyond Earth.”
That may prove challenging in an arena that has been characterized by intense geopolitical competition. But we have a golden opportunity to avoid the same mistakes we have made here on Earth.
The post Scientists Say We Need a Circular Space Economy to Avoid Trashing Orbit appeared first on SingularityHub.
2025-11-30 04:29:19
The AI Boom Is Based on a Fundamental MistakeBenjamin Riley | The Verge
“The problem is that according to current neuroscience, human thinking is largely independent of human language—and we have little reason to believe ever more sophisticated modeling of language will create a form of intelligence that meets or surpasses our own.”
Why Google’s Custom AI Chips Are Shaking Up the Tech IndustryAlex Wilkins | New Scientist ($)
“Nvidia’s position as the dominant supplier of AI chips may be under threat from a specialized chip pioneered by Google, with reports suggesting companies like Meta and Anthropic are looking to spend billions on Google’s tensor processing units.”
What’s Next for AlphaFold: A Conversation With a Google DeepMind Nobel LaureateWill Douglas Heaven | MIT Technology Review ($)
“It was five years ago this week that AlphaFold 2’s debut took scientists by surprise. Now that the hype has died down, what impact has AlphaFold really had? How are scientists using it? And what’s next? I talked to Jumper (as well as a few other scientists) to find out.”
A Humanoid Robot-Shaped Bubble Is Forming, China WarnsRobert Hart | The Verge
“Speaking at a press briefing, National Development and Reform Commission spokesperson Li Chao said China’s humanoid robotics industry needs to balance ‘the speed of growth against the risk of bubbles.’ Investment has been pouring into the sector despite there being few proven use cases for the bots, Li said, risking a flood of ‘highly similar’ models as funding for research and development shrinks.”
Supermassive Dark Matter Stars May Be Lurking in the Early UniverseLeah Crane | New Scientist ($)
“We may have seen the first hints of strange stars powered by dark matter. These so-called dark stars could explain several of the most mysterious objects in the universe, while also giving us hints about the true nature of dark matter itself.”
Crypto Winter Will Be Different This TimeKen Brown | The Information ($)
“[Stablecoins’] broader use also creates more ways for a stablecoin crisis to emerge and spread across the globe. It is here that the links to the traditional financial system matter. If investors dump their stablecoins, as they did with Circle, the companies sell the assets that back them, potentially causing turmoil in Treasurys, money markets, and the like.”
MIT Study Finds AI Is Already Capable of Replacing 11.7% of US WorkersGrace Snelling | Fast Company
“In an interview with CNBC, Prasanna Balaprakash, ORNL director and co-leader of the research, described [the Iceberg Index model] as a ‘digital twin for the US labor market.’ Using that base of data, the index analyzes to what extent digital AI tools can already perform certain technical and cognitive tasks, and then produces an estimate of what AI exposure in each area looks like.”
AI Isn’t Just Automating Jobs. It’s Creating New Layers of Human WorkEnrique Dans | Fast Company
“When an AI drafts a report, someone still has to verify its claims (please, do not forget this!), check for bias, and rewrite the parts that don’t sound right. When an agent summarizes a meeting, someone has to decide what actually matters. Automation doesn’t erase labor; it just moves it upstream, from execution to supervision.”
The First Large-Scale Cyberattack by AINury Turkel | The Wall Street Journal ($)
“A state-backed threat group, likely Chinese, crossed a threshold in September that cybersecurity experts have warned about for years. According to a report by Anthropic, attackers manipulated its AI system, Claude Code, to conduct what appears to be the first large-scale espionage operation executed primarily by artificial intelligence.”
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2025-11-28 23:00:00
Behavior can be deceptive. What matters for consciousness is not what you do, but how you do it.
You might think a honey bee foraging in your garden and a browser window running ChatGPT have nothing in common. But recent scientific research has been seriously considering the possibility that either, or both, might be conscious.
There are many different ways of studying consciousness. One of the most common is to measure how an animal—or artificial intelligence—acts.
But two new papers on the possibility of consciousness in animals and AI suggest new theories for how to test this—one that strikes a middle ground between sensationalism and knee-jerk skepticism about whether humans are the only conscious beings on Earth.
Questions around consciousness have long sparked fierce debate.
That’s in part because conscious beings might matter morally in a way that unconscious things don’t. Expanding the sphere of consciousness means expanding our ethical horizons. Even if we can’t be sure something is conscious, we might err on the side of caution by assuming it is—what philosopher Jonathan Birch calls the precautionary principle for sentience.
The recent trend has been one of expansion.
For example, in April 2024 a group of 40 scientists at a conference in New York proposed the New York Declaration on Animal Consciousness. Subsequently signed by over 500 scientists and philosophers, this declaration says consciousness is realistically possible in all vertebrates (including reptiles, amphibians and fishes) as well as many invertebrates, including cephalopods (octopus and squid), crustaceans (crabs and lobsters) and insects.
In parallel with this, the incredible rise of large language models, such as ChatGPT, has raised the serious possibility that machines may be conscious.
Five years ago, a seemingly ironclad test of whether something was conscious was to see if you could have a conversation with it. Philosopher Susan Schneider suggested if we had an AI that convincingly mused on the metaphysics of consciousness, it may well be conscious.
By those standards, today we would be surrounded by conscious machines. Many have gone so far as to apply the precautionary principle here too: the burgeoning field of AI welfare is devoted to figuring out if and when we must care about machines.
Yet all of these arguments depend, in large part, on surface-level behavior. But that behavior can be deceptive. What matters for consciousness is not what you do, but how you do it.
A new paper in Trends in Cognitive Sciences that one of us (Colin Klein) coauthored, drawing on previous work, looks to the machinery rather than the behavior of AI.
It also draws on the cognitive science tradition to identify a plausible list of indicators of consciousness based on the structure of information processing. This means one can draw up a useful list of indicators of consciousness without having to agree on which of the current cognitive theories of consciousness is correct.
Some indicators (such as the need to resolve trade-offs between competing goals in contextually appropriate ways) are shared by many theories. Most other indicators (such as the presence of informational feedback) are only required by one theory but indicative in others.
Importantly, the useful indicators are all structural. They all have to do with how brains and computers process and combine information.
The verdict? No existing AI system (including ChatGPT) is conscious. The appearance of consciousness in large language models is not achieved in a way that is sufficiently similar to us to warrant attribution of conscious states.
Yet at the same time, there is no bar to AI systems—perhaps ones with a very different architecture to today’s systems—becoming conscious.
The lesson? It’s possible for AI to behave as if conscious without being conscious.
Biologists are also turning to mechanisms—how brains work—to recognize consciousness in non-human animals.
In a new paper in Philosophical Transactions B, we propose a neural model for minimal consciousness in insects. This is a model that abstracts away from anatomical detail to focus on the core computations done by simple brains.
Our key insight is to identify the kind of computation our brains perform that gives rise to experience.
This computation solves ancient problems from our evolutionary history that arise from having a mobile, complex body with many senses and conflicting needs.
Importantly, we don’t identify the computation itself—there is science yet to be done. But we show that if you could identify it, you’d have a level playing field to compare humans, invertebrates, and computers.
The problem of consciousness in animals and in computers appear to pull in different directions.
For animals, the question is often how to interpret whether ambiguous behavior (like a crab tending its wounds) indicates consciousness.
For computers, we have to decide whether apparently unambiguous behavior (a chatbot musing with you on the purpose of existence) is a true indicator of consciousness or mere roleplay.
Yet as the fields of neuroscience and AI progress, both are converging on the same lesson: when making judgement about whether something is consciousness, how it works is proving more informative than what it does.
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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2025-11-27 23:00:00
A range of CRISPR gene therapies are taking aim at chronically high cholesterol, reducing the risk of heart disease.
The gene editor CRISPR is tackling fatty molecules in the body that contribute to one of the world’s top killers: cardiovascular disease.
At the American Heart Association Scientific Sessions 2025 (AHA 2025) this month, Scribe Therapeutics, a startup based in Alameda, California, presented three CRISPR formulations that slashed dangerously high lipid levels in lab-grown cells, mice, and monkeys.
With a single injection, their flagship formulation lowered “bad cholesterol” levels in primates for over 515 days. The treatment used a type of genetic manipulation called epigenome editing that doesn’t directly change the genetic code, potentially reducing side effects.
Two other CRISPR formulations targeted lipoprotein(a) and triglycerides, both fatty substances that form clumps inside blood vessels when at high levels. An injection in mice slashed the molecules by over 95 percent in early trials.
The therapies join other emerging efforts using CRISPR to tackle cardiovascular disease. If the results translate to humans, a daily pill—often taken for decades—may become a thing of the past.
“These results demonstrate that comprehensive engineering of CRISPR technologies can produce medicines with markedly improved safety and performance, surpassing the limitations of early Cas9-based systems,” Benjamin Oakes, cofounder and CEO of Scribe, said in a press release.
High cholesterol haunts millions of Americans. A silent killer, the fatty molecules clog up blood vessels and raise the risk of heart attack, vascular disease, and stroke. Physicians recommend daily statins and dietary changes to manage cholesterol levels, but the regime is hard to follow—especially for years or decades.
Cholesterol comes in multiple forms. Some of these protect the heart and blood vessels. Others lead to clogged arteries. LDL, or low-density lipoprotein, normally transports molecules from the liver to the body’s cells to maintain essential functions, such as building membranes, producing hormones, and creating vitamin D. Too much LDL, however, leads to a buildup of plaques that harden blood vessels and narrow their diameter. This means the heart must work harder to pump blood through the body.
After years of research, scientists identified a gene called PCSK9 that, if overactive, increases the levels of LDL circulating in the blood. FDA-approved drugs that inhibit the PCSK9 protein show promise for lowering cholesterol. But inhibiting the gene itself could offer a longer-term solution.
There have been early successes. In 2023, a small clinical trial in people genetically prone to dangerously high levels of cholesterol found a single infusion of a precise gene editor decreased artery-clogging fat by almost half. Participants had a single mutated DNA letter in the PCSK9 gene that caused their LDL levels to skyrocket. Using base editing—a version of CRISPR—the team engineered a therapy to correct the genetic typo.
A similar strategy could also benefit other populations with high cholesterol. However, base editing permanently alters the genome and could trigger unexpected DNA changes.
Enter epigenetic editors. Rather than directly altering DNA letters, this technology targets the molecular machinery that switches genes on or off. Because epigenetic editors don’t directly change the genetic code, the approach could potentially be safer than gene editing.
Last year, one team employed designer molecules called zinc-finger proteins, a favorite gene-editing tool predating CRISPR, to shut down PCSK9 without changing the gene itself. A single injection slashed cholesterol levels in mice and kept them low for nearly a year—roughly half the mice’s lifespan.
AHA 2025 built on those results.
Scribe developed an epigenetic silencer to suppress PCSK9 using CRISPR-CasX. Like the original version, CRISPR-Cas9, CRISPR-CasX has a guide RNA that tethers CasX—a tiny scissor enzyme—to genes involved in regulating PCSK9 activity and shuts them down.
In monkeys, a single infusion of the treatment slashed LDL levels up to 68 percent. Unlike DNA edits, epigenetic modifications are often lost when cells divide, meaning the drug could lose efficacy over time, especially in rapidly regenerating organs like the liver. But the monkey’s LDL levels remained low for over 515 days without otherwise stressing their livers. Also, the drug didn’t notably change the activity of other genes in cultured human liver cells, suggesting it’s precise.
The data strengthens “the case for a new class of durable epigenetic medicines for large patient populations,” wrote the company in a press release.
PCSK9 isn’t the only gene involved in heart disease. CRISPR Therapeutics, headquartered in Switzerland, worked with the Cleveland Clinic Foundation to find another gene related to high cholesterol levels: ANGPTL3. Studies show people born with dysfunctional versions of the gene naturally have lower LDL levels and risk of heart disease.
The team used CRISPR-Cas9 to disable the gene and recruited 15 people with various blood lipid diseases to test the treatment’s safety profile. Two weeks after a shot, participants’ ANGPTL3 protein and LDL levels dropped significantly and remained low for at least 60 days. Results from the trial, also presented at AHA 2015, found that the treatment was well tolerated overall.
“This is really unprecedented,” said author Luke J. Laffin in a press briefing. “If confirmed in larger trials, this one-and-done approach could transform care for people with lifelong lipid disorders and dramatically reduce cardiovascular risk.”
Artery-blocking lipids beyond LDL are now also in CRISPR’s crosshairs.
Lipoprotein(a) is a mysterious nanoball of fat that’s somewhat similar to LDL in structure but with a more complex mix of components. The substance deposits cholesterol as it roams blood vessels—including smaller ones involved in healing and regeneration. An estimated 30 percent of people worldwide have abnormally high levels of lipoprotein(a). This is mainly due to genetic risks and is hard to reverse with dietary changes or medication.
Another CRISPR-based technology is showing promise here. At the conference, Scribe said its in-house CasXE gene editor inactivates a gene that makes Lp(a) in liver cells. In mice, a single injection slashed levels of the fatty balls by up to 95 percent, with no detectable off-target editing.
Finally, the company showcased a different CasXE gene editor that kneecaps a gene associated with lipid production. Like other genetic targets, people with naturally lower levels of the gene APOC3 have low levels of blood lipids and lower risk of heart disease. One shot edited over 75 percent of all liver cells in monkeys and almost completely reversed high blood lipid levels in mice.
These are all preliminary results, but they could lead to a quantum shift in managing a global chronic disease with a single shot instead of daily pills.
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