Right side heart failure. Credit: Scientific Animations CC4.0
An early clinical study shows that a new oral drug is safe and well-tolerated in patients with chronic heart failure. The study, led by researchers at Karolinska Institutet, has been published in the scientific journal The Lancet.
Heart failure with reduced pumping capacity means that the heart struggles to pump blood effectively around the body. Despite current treatments, many patients’ condition worsens over time, and existing drugs that strengthen the heart’s contractions can cause serious side effects, such as heart rhythm disturbances and changes in blood pressure.
In the study, researchers investigated a new drug, AC01, which targets the body’s ghrelin receptor. Ghrelin is a hormone that influences metabolism and growth hormone release, and its receptor is also found in heart muscle. AC01 is intended to strengthen the heart’s pumping ability through a different biological mechanism from traditional heart‑stimulating drugs, thereby reducing the risk of side effects.
The study was a randomised, placebo‑controlled phase 1b/2a trial involving 58 patients with stable, chronic heart failure with reduced pumping capacity. Participants received different doses of AC01 or placebo for either seven or 28 days. The main aim was to assess safety and tolerability.
The drug was well tolerated
The results show that the drug was well tolerated. No serious side effects linked to AC01 were reported. The researchers also found no signs of harmful effects on heart rhythm or blood pressure. Exploratory analyses additionally indicated signs of improved heart function, such as increased stroke volume and cardiac output.
“This is an early study with a limited number of patients, but the results suggest that AC01 can be administered safely to people with heart failure. The findings now justify further studies to investigate whether the signals of improved heart function that we have observed can lead to clinical benefit in larger and longer studies,” says Lars Lund, first author and professor at the Department of Medicine, Solna, Karolinska Institutet, and senior consultant cardiologist at Karolinska University Hospital.
Scientists at Bath and King’s College London have discovered that a common chemical could be used to develop a new treatment for difficult-to-treat nail infections.
Paronychia. Source: Wikimedia Commons CC0
Hydrogen sulphide, the volcanic gas that smells of rotten eggs, could be used in a new treatment for tricky nail infections that acts faster but with fewer side effects, according to scientists at the University of Bath and King’s College London (KCL).
Nail infections are mostly caused by fungi and occasionally by bacteria. They are very common, affecting between 4-10% of the global population, rising to nearly half those aged 70 or over.
These infections can lead to complications, particularly in vulnerable groups such as diabetics and the elderly, but are notoriously difficult to treat.
Current treatments include oral antifungals taken in pill form, and topical treatments which are applied directly to the nail.
Oral antifungals take around 2-4 months to act and are reasonably effective, but they carry risks of side effects, especially in patients with other medical conditions.
Treatments applied directly to the nail are safer, but they often take much longer to work, sometimes taking even years to work, and they frequently relapse or fail.
This is largely because it’s very difficult to get the drug to penetrate through the nail to where the infection resides.
Even the most effective topical treatments have relatively low cure rates, so there is a clear need for new therapeutic approaches that are safe, effective, and capable of reaching microbes embedded deep within the nail.
A team from the University of Bath and King’s College London has now found that hydrogen sulphide (H₂S), a small, naturally occurring gas, could be developed into a promising new treatment.
Previous work has shown that it penetrates the nail plate far more efficiently than existing topical drugs, and now the team has demonstrated that it has strong antimicrobial activity against a wide range of nail pathogens, including fungi that are resistant to common antifungal treatments.
In laboratory tests, the team used a chemical that breaks down to release the H₂S gas and found that it acts in a unique way, disrupting microbial energy production and triggering irreversible damage, ultimately killing the fungi.
Dr Albert Bolhuis, from the University of Bath’s Department of Life Sciences, said: “Thanks to its ability to efficiently reach the site of infection and its novel mode of action, we believe that a topically applied medicine containing hydrogen sulphide could become a highly effective new treatment for nail infections, which avoids the limitations of current therapies.
“Our research lays the foundation for a compelling alternative to existing treatments, with the potential to improve outcomes for patients suffering from persistent and drug-resistant fungal nail infections.”
Hydrogen sulphide is known for its pungent smell of rotten eggs, and has some toxicity, however researchers believe the amounts required are well below toxicity levels and the correct formulation will limit any unpleasant odours.
The research has so far only been done in vitro, but the team hopes to develop a treatment that could be used in patients in the next five years.
Professor Stuart Jones, Director of the Centre for Pharmaceutical Medicine Research at KCL said: “We are looking forward to translating these findings into an innovative topical product that can treat nail infection.”
Imagine knowing in your 20s or 30s that you carry a gene which will cause your mind and body to slowly unravel. Huntington’s disease is inherited, relentless and fatal, and there is no cure. Families live with the certainty of decline stretching across generations.
Now, a new treatment is being widely reported as a breakthrough.
Last week, gene therapy company uniQure announced that a one-time brain infusion appeared to slow the disease in a small clinical study.
If confirmed, this would not only be a landmark for Huntington’s disease but potentially the first time a gene therapy has shown promise in any adult-onset neurodegenerative disorder.
But the results, which were announced in a press release, are early, unreviewed and based on external comparisons. So, while these findings offer families hope after decades of failure, we need to remain cautious.
Symptoms usually start in mid-life. They include involuntary movements, depression, irritability and progressive decline in thinking and memory. People lose the ability to work, manage money, live independently and eventually care for themselves. Most die ten to 20 years after onset.
The disease is caused by an expanded stretch of certain DNA repeats (CAG) in the huntingtin gene. The number of repeats strongly influences when symptoms begin, with longer expansions usually linked to earlier onset.
Looking for a treatment
The gene that causes Huntington’s disease was identified in 1993, 32 years ago. Soon afterwards, mouse studies showed that switching off the mutant huntingtin protein even after symptoms had begun could reverse signs and improve behaviour.
This suggested lowering the toxic protein might slow or even partly reverse the disease. Yet for three decades, every attempt to develop a therapy for people has failed to show convincing clinical benefit. Trials of huntingtin-lowering drugs and other approaches did not slow progression.
What is the new treatment?
The one-time gene therapy, called AMT-130, involves brain surgery guided by MRI. Surgeons infuse an engineered virus directly into the caudate and putamen brain regions, which are heavily affected in Huntington’s.
The virus carries a short genetic “microRNA” designed to reduce production of the affected huntingtin protein.
By delivering it straight into the brain, the treatment bypasses the blood–brain barrier. This natural wall usually prevents medicines from entering the central nervous system. That barrier helps explain why so many brain-targeted drugs have failed.
What did they find?
Some 29 patients received treatment, with 12 in each group (one low-dose, and one high-dose) followed for three years. According to uniQure, those given the higher dose declined much slower than expected.
The study compared how much participants’ movement, thinking and daily function declined, compared to a matched external group from a global Huntington’s registry (meaning they weren’t part of the study). The company claimed those given the higher dose had a 75% slowing in their decline.
On a functional scale focused on independence, the company reported a 60% slowing in decline for the higher dose group.
Other tests of movement and thinking also favoured treatment. Nerve-cell damage in spinal fluid was lower for study participants than would be expected for untreated patients.
Why should we be cautious?
These findings are an early snapshot of results reported by the company, not yet peer-reviewed. The study compared treated patients to an external matched control group, not people randomised to placebo at the same time. This design can introduce bias. The numbers are also small – only 12 patients at the three-year mark – so we can’t draw solid conclusions.
The company reports the therapy was generally well tolerated, with no new serious adverse events related to the drug since late 2022. Most problems were related to the neurosurgical infusion itself, and resolved. But in a disease that already causes such severe symptoms, it is often hard to know what counts as a side effect.
The company uniQure has said it plans to seek regulatory approval in 2026 on the basis of this dataset.
Regulators will face difficult decisions: whether to allow access sooner before all the questions and uncertainties are addressed – based on the needs of a community with no effective options – and wait for further data while people are being treated, or to insist on larger trials that confirm results before approval.
What does it mean?
If upheld, these results represent the first convincing signs that a gene-targeted therapy can slow Huntington’s disease. They may also be the first evidence of benefit from a gene therapy in any adult-onset neurodegenerative disorder. That would be a milestone after decades of failure.
But these results do not prove success. Only larger, longer and fully peer-reviewed studies will show whether this treatment truly changes lives. Even if approved, a complex neurosurgical gene therapy may not be easily accessible to all patients.
The company has said the drug’s price would be similar to other gene therapies – which can cost over A$3 million per patient – and will have the added cost of brain surgery.
The takeaway
For families who carry this gene, the hope is profound. But caution is just as important.
We may be witnessing the first credible step toward slowing an inherited adult-onset neurodegenerative disease, or just an early signal that may not hold up.
Ultimately, only time and rigorous science will show whether this treatment delivers the benefits so urgently needed.
A study published in Nature Structural & Molecular Biology is the first time researchers have shown evidence that a single drug, already licensed for medical use, can stabilise nearly all mutated versions of a human protein, regardless of where the mutation is in the sequence.
The researchers engineered seven thousand versions of the vasopressin V2 receptor (V2R), which is critical for normal kidney function, creating all possible mutated variants in the lab. Faulty mutations in V2R prevent kidney cells from responding to the hormone vasopressin, leading to the inability to concentrate urine and resulting in excessive thirst and large volumes of dilute urine, causing nephrogenic diabetes insipidus (NDI), also known as arginine vasopressin resistance, a rare disease affecting roughly one in 25 000 people.
When they carried out further experiments looking specifically at mutations observed in patients, they found that the oral medicine tolvaptan, clinically-approved for other kidney conditions, restored receptor levels to near-normal for 87 per cent of destabilised mutations (60 out of 69 known disease-causing mutations, and 835 out of 965 predicted disease-causing mutations).
“Inside the cell, V2R travels through a tightly managed traffic system. Mutations cause a jam, so V2R never reaches the surface. Tolvaptan steadies the receptor for long enough to allow the cell’s quality control system to wave it through,” explains Dr. Taylor Mighell, first author of the study and postdoctoral researcher at the Centre for Genomic Regulation (CRG) in Barcelona.
The research group have previously shown that most mutations affect a protein’s function by altering its stability, making the whole structure wobblier than normal. According to the authors of the study, tolvaptan works regardless of where the mutation is because proteins switch between folded and unfolded forms. Most V2R mutations make the unfolded form more likely. When tolvaptan binds to V2R, it favours the folded form over the unfolded one.
The research is the first proof-of-principle study to demonstrate that a drug can act like a “nearly universal” pharmacological chaperone, meaning it can latch onto a protein and stabilise the structure regardless of where it’s mutated, in this case, in nearly nine out of ten cases.
The findings could help tackle a longstanding challenge in rare disease medicine. A rare disease is any disease affecting fewer than 1 in 2000 people. Though individual prevalence is low, rare diseases are a formidable challenge for global health because there are thousands of different types, meaning around 300 million people worldwide live with a rare condition.
Most rare diseases are caused by mutations in DNA. The same gene can be mutated in many ways, so patients with “the same” rare disease can have different mutations driving the condition. Because few individuals will have the same mutation, drug development is slow and commercially unattractive. Most treatments help manage symptoms rather than tackling the root cause of a rare disease.
Previous studies show that between 40 and 60% of rare-disease causing mutations affect a protein’s stability. If future studies confirm the rescued receptors work normally, the study offers a new roadmap for rare-disease drug development. Rather than look for a drug that targets a single mutation, researchers could instead look for one that targets stabilising an entire protein.
V2R is part of the human body’s largest family of receptors, also known as G-protein-coupled receptors (GPCRs). These roughly 800 genes are the targets of about a third of all approved drugs. Many rare and common diseases arise when GPCRs don’t fold or traffic correctly to the cell surface, even though their signalling parts are largely intact.
“If the behaviour we found holds for others members of GPCR family, drug developers could swap spending years of hunting for bespoke therapeutic molecules and try looking for general or universal pharmacological chaperones instead, greatly accelerating the drug development pipeline for many genetic diseases,” concludes ICREA Research Professor Ben Lehner, Group Leader at the Wellcome Sanger Institute (Hinxton, UK) and Centre for Genomic Regulation (Barcelona).
In a potential game-changer for how we treat the flu, scientists at the Hebrew University of Jerusalem have unveiled a new drug pairing that outperforms oseltamivir – the most widely used anti-influenza medication – against even the deadliest flu strains, including bird(avian) and swine flu.
The surprising duo? One of them is theobromine, a compound found in chocolate.
In a study recently published in PNAS, researchers, led by Prof Isaiah (Shy) Arkin, have developed a novel combination therapy that targets a key weakness in the influenza virus: its ion channel, a microscopic gate the virus uses to replicate and spread. By blocking this gate, the team effectively cut off the virus’s ability to survive.
Their study, conducted at Israel’s new Barry Skolnick Biosafety Level 3 facility, tested this combo, consisting of theobromine and a lesser-known compound called arainosine, against a broad range of flu viruses. In both cell cultures and animal trials, the treatment dramatically outperformed oseltamivir (Tamiflu), especially against drug-resistant strains.
“We’re not just offering a better flu drug,” said Prof Arkin. “We’re introducing a new way to target viruses – one that may help us prepare for future pandemics.”
Why It Matters
The stakes are high: Influenza continues to sweep the globe each year, with unpredictable mutations that challenge vaccines and existing drugs. In the U.S. alone, seasonal flu costs an estimated $87 billion annually in healthcare and lost productivity. Past pandemics – like the 2009 swine flu – have inflicted even deeper global costs, and the cost of future pandemics was estimated to rise even further up to $4.4 trillion.
Meanwhile, outbreaks of avian flu have devastated poultry industries and sparked fears of cross-species transmission to humans. Just one recent outbreak in the U.S. led to the loss of 40 million birds and billions in economic damage.
Current flu treatments, like oseltamivir, are losing ground as the virus adapts. Most drugs in use target a viral protein that mutates frequently, rendering treatments less effective over time. That’s where Arkin’s team saw an opening.
A New Strategy for Old Viruses
Instead of fighting the virus head-on with traditional antivirals, the researchers zeroed in on the M2 ion channel – a crucial viral feature that helps the virus replicate. Past efforts to block this channel have largely failed due to drug resistance. But the new theobromine–arainosine combo sidesteps this resistance, even neutralising hard-to-treat strains.
The team discovered the combo by scanning a library of repurposed compounds, many originally developed for other diseases, and testing their effects on both drug-sensitive and drug-resistant versions of the virus.
Broader Implications
The implications extend beyond influenza. Because many viruses, including coronaviruses, also rely on ion channels, this new approach could form the basis of future antiviral strategies.
The next steps include human clinical trials, but the early results offer hope not just for a better flu treatment, but for a smarter way to fight viral disease in general. ViroBlock, a startup company emanating from the Hebrew University, has been entrusted to develop the discoveries to reach the public.
Paracetamol (acetaminophen) is one of the most common painkillers and is found in hundreds of different medications. While safe at recommended doses, paracetamol overdose is the leading cause of acute liver injury in the U.S. Now, researchers propose that a new molecule has the potential to treat acetaminophen-induced liver injury (AILI) and other inflammatory conditions. They conducted a small-scale mouse trial and found that the new compound decreased AILI-caused liver inflammation and prevented liver damage.
Jannatun Nayem Namme, a graduate student at Virginia Commonwealth University, will present her team’s results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2025 is being held Aug. 17-21; it features about 9000 presentations on a range of science topics.
Most acetaminophen overdoses are accidental, often due to people unintentionally consuming multiple products containing the painkiller or misinterpreting dosage. After taking a recommended amount of paracetamol, a person’s liver converts a small percentage of it into a toxic molecule called N-acetyl-p-benzoquinone imine (NAPQI). Normally, the liver can quickly metabolise NAPQI into a non-toxic form. But if a person takes too much acetaminophen, NAPQI builds up and causes irreversible cell damage, leading to liver injury or death. Currently, N-acetylcysteine is the only drug available to treat AILI, and it must be administered within eight hours of overdose.
To develop novel treatments for inflammatory conditions, such as AILI, and neurodegenerative conditions, Namme and her colleagues previously focused on small molecules that reduce the activity of inflammation-causing proteins, known as inflammasomes. Inflammasomes are also involved in pyroptosis, a type of cellular death associated with AILI. While developing inflammasome inhibitors, the researchers noticed that some of the compounds they created could target a specific inflammatory protein called gasdermin D (GSDMD). GSDMD is involved in pyroptosis.
Namme and the team synthesised several different GSDMD-inhibiting compounds and tested them for their ability to bind to GSDMD. They discovered that one small molecule, which they labelled YM81, selectively binds to and inhibits GSDMD from initiating pyroptosis.
Next, the researchers treated five mice with AILI using YM81 and compared them to 10 mice given a placebo. They monitored the extent of liver damage in the animals 17 hours after the acetaminophen overdose. Compared to the placebo group, mice treated with YM81 had significantly lower levels of alanine transaminase and aspartate transaminase, two liver injury biomarkers. These results indicate that the YM81 treatment helped decrease liver inflammation by inhibiting GSDMD.
Shijun Zhang, the study’s principal investigator, says that YM81 is in the early stages of drug development. “In the future, we will focus on optimising YM81 to increase its potency, safety and stability, in addition to exploring its therapeutic potential in additional animal models,” he says.
Namme adds that GSDMD inhibitors like YM81 have the potential to treat other inflammatory conditions. “GSDMD is a common protein involved in multiple inflammatory and neurodegenerative diseases, such as arthritis, sepsis and gout,” she says. “Targeting GSDMD could offer a therapeutic strategy to reduce the inflammation and damage from multiple diseases and causes.”
A new weekly injectable drug could transform the lives of more than eight million people living with Parkinson’s disease, potentially replacing the need for multiple daily tablets.
UniSA PhD candidate Deepa Nakmode and Professor Sanjay Garg in the lab. Credit: UniSA
Scientists from the University of South Australia (UniSA) have developed a long-acting injectable formulation that delivers a steady dose of levodopa and carbidopa – two key medications for Parkinson’s – over an entire week.
The biodegradable formulation is delivered in a subcutaneous or intramuscular injection, where it gradually releases the medication over seven days.
Parkinson’s disease is the second most common neurological disorder, affecting more than 8.5 million people worldwide. Currently there is no cure and the symptoms – tremors, rigidity and slow movement – are managed with oral medications that must be taken several times a day.
The frequent dosing is a burden, especially for elderly patients or those with swallowing difficulties, leading to inconsistent medication levels, more side effects, and reduced effectiveness.
Lead researcher Professor Sanjay Garg, from UniSA’s Centre for Pharmaceutical Innovation, says the newly developed injectable could significantly improve treatment outcomes and patient adherence.
“Our goal was to create a formulation that simplifies treatment, improves patient compliance, and maintains consistent therapeutic levels of medication. This weekly injection could be a game-changer for Parkinson’s care,” Prof Garg says.
“Levodopa is the gold-standard therapy for Parkinson’s, but its short life span means it must be taken several times a day.”
UniSA PhD student Deepa Nakmode says the in-situ implant is designed to release both levodopa and carbidopa steadily over one week, maintaining consistent plasma levels and reducing the risks associated with fluctuating drug concentrations.
“After years of focused research, it’s incredibly rewarding to see our innovation in long-acting injectables for Parkinson’s disease reach this stage. Our invention has now been filed for an Australian patent,” Nakmode says.
The injectable gel combines an FDA-approved biodegradable polymer PLGA with Eudragit L-100, a pH-sensitive polymer, to achieve a controlled and sustained drug release.
Extensive lab tests confirmed the system’s effectiveness and safety:
More than 90% of the levodopa dose and more than 81% of the carbidopa dose was released over seven days.
The implant degraded by over 80% within a week and showed no significant toxicity in cell viability tests.
The formulation can be easily administered through a fine 22-gauge needle, minimising discomfort and eliminating the need for surgical implant.
“The implications of this research are profound,” Prof Garg says. “By reducing the frequency of dosing from multiple times a day to a weekly injection is a major step forward in Parkinson’s therapy. We’re not just improving how the drug is delivered; we’re improving patients’ lives.”
Prof Garg says the technology could also be adapted for other chronic conditions such as cancer, diabetes, neurodegenerative disorders, pain management, and chronic infections that require long-term drug delivery.in
The system can be tuned to release drugs over a period ranging from a few days to several weeks depending on therapeutic needs.
UniSA scientists hope to start clinical trials in the near future and are exploring commercialisation opportunities.
ALS — also often called Lou Gehrig’s disease — is a progressive, neurodegenerative disease with no cure. Despite its devastating impact, the pace of new therapy development has remained sluggish—largely due to the high cost, duration, and risks associated with traditional clinical trials. This bottleneck has often discouraged conventional investors, leaving promising research to languish.
To tackle this challenge, the authors propose an investment fund that finances half the cost of an adaptive platform trial in exchange for future royalties from successful drugs that emerge from the trial. Adaptive platform trials allow multiple drug candidates to be tested simultaneously under a single master protocol, and results are interpreted on a real-time basis to determine efficacy or futility. Drawing on data from the HEALEY ALS Platform Trial administered by the Healey & AMG Center for ALS at MGH, and realistic assumptions, their simulated fund generated an expected return of 28%, with a 22% probability of total loss, which may be attractive to more risk-tolerant and impact-driven investors such as hedge funds, sovereign wealth funds, family offices, and philanthropists. Their findings suggest that generating returns more palatable for mainstream investors could be achieved by funding multiple platform trials simultaneously and by employing financial tools such as securitization — a method that bundles future income from assets like loans or royalties into investment products.
“ALS clinical trials face significant hurdles — from high costs and long timelines to limited funding pools,” said Merit E. Cudkowicz, MD, MSC, Executive Director at Mass General Brigham Neuroscience Institute and Director of the Healey & AMG Center for ALS. “Our platform trial model has already shown that we can test more therapies more efficiently. What’s still missing is sustainable financing. This novel approach could be a game-changer, enabling us to launch trials faster, include more promising therapies, and bring us closer to our shared goal: delivering effective treatments to people with ALS as quickly as possible.”
While their study focused on ALS, the authors believe such a funding model could be applied to other disease areas as well, especially those with well-defined endpoints, where treatment success can be measured clearly and reliably.
Retina showing reticular pseudodrusen. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Credit: National Eye Institute
A new study from Washington University School of Medicine in St. Louis identifies a possible way to slow or block progression of age-related macular degeneration, a leading cause of blindness in people over age 50. The WashU Medicine researchers and their international collaborators implicated problems with cholesterol metabolism in this type of vision loss, perhaps helping to explain the links between macular degeneration and cardiovascular disease, which both worsen with age.
The new findings, using human plasma samples and mouse models of macular degeneration, suggest that increasing the amount of a molecule called apolipoprotein M (ApoM) in the blood fixes problems in cholesterol processing that lead to cellular damage in the eyes and other organs. Various methods of dialing up ApoM could serve as new treatment strategies for age-related macular degeneration and perhaps some forms of heart failure triggered by similar dysfunctional cholesterol processing.
“Our study points to a possible way to address a major unmet clinical need,” said senior author Rajendra S. Apte, MD, PhD, professor of ophthalmology and visual sciences at WashU Medicine. “Current therapies that reduce the chance of further vision loss are limited to only the most advanced stages of macular degeneration and do not reverse the disease. Our findings suggest that developing treatments that increase ApoM levels could treat or even prevent the disease and therefore preserve people’s vision as they age.”
In macular degeneration, doctors can see cholesterol-rich deposits under the retina during an eye exam, according to Apte. In early stages, vision might still be normal, but the deposits increase inflammation and other damaging processes the lead to the gradual loss of central vision. In the most common type, “dry” macular degeneration, the cells in the central part of the retina can be damaged, causing a type of neurodegeneration called geographic atrophy, which is similar to what happens in the brain in conditions such as Alzheimer’s disease. Dry macular degeneration can turn into “wet” macular degeneration, in which abnormal blood vessel growth damages vision.
Geographic atrophy and wet macular degeneration are advanced forms of the disease that are accompanied by vision loss. Although some approved therapies for advanced disease are available, the disease process itself is not reversible at that stage.
A common culprit in eye disease and heart failure
In recent years, evidence has emerged that ApoM can serve as a protective molecule with known anti-inflammatory effects and roles in maintaining healthy cholesterol metabolism. With that in mind, Apte and co-senior author Ali Javaheri, MD, PhD, an assistant professor of medicine, were interested in assessing whether reduced ApoM levels, which fall with age, could be involved in the dysfunctional cholesterol metabolism that is at the root of multiple diseases of aging, including macular degeneration and heart disease. They showed that patients with macular degeneration have reduced levels of ApoM circulating in the blood compared with healthy controls. And past work by Javaheri, a WashU Medicine cardiologist, showed that patients with various forms of heart failure also had reduced levels of ApoM in the blood.
This study revealed that ApoM is a key component in the “good cholesterol” pathways that mop up excess “bad” LDL cholesterol and excrete it via the liver.
Apte and Javaheri’s research suggests that when ApoM is low, cells in the retina and heart muscle can’t correctly metabolise cholesterol deposits and struggle to clear these accumulating lipids. When these lipids build up, it leads to inflammation and cellular damage.
To see if they could reverse the harmful effects of low ApoM, the researchers increased ApoM levels in mouse models of macular degeneration, using genetic modification or plasma transfer from other mice. The mice showed evidence of improved retinal health, improved function of light-sensing cells in the retina and reduced accumulation of cholesterol deposits. The researchers further found evidence that ApoM triggers a signalling pathway that breaks down the cholesterol in cellular compartments called lysosomes, which are known for playing important roles in disposing of cellular waste.
The researchers also found that ApoM must be bound to a molecule called sphingosine-1-phosphate (S1P) to get the beneficial effects of ApoM treatment in the mice.
The findings also could have implications for future interventions that raise ApoM in patients with heart failure.
“One of the exciting things about this collaboration is realising the links between retinal pigment epithelial cells and heart muscle cell, which are both vulnerable to low ApoM,” Javeheri said. “It is possible that the interaction between ApoM and S1P is regulating cholesterol metabolism in both cell types. We look forward to exploring strategies to increase ApoM in ways that could help the eye and the heart maintain healthy cholesterol metabolism over time and stave off two major diseases of aging.”
A sample of Aspergillus flavus cultured in the Gao Lab. (Credit: Bella Ciervo)
University of Pennsylvania-led researchers have turned a deadly fungus into a potent cancer-fighting compound. After isolating a new class of molecules from Aspergillus flavus, a toxic crop fungus linked to deaths in excavating ancient tombs, the researchers modified the chemicals and tested them against leukaemia cells. The result was a promising cancer-killing compound that rivals FDA-approved drugs and opens up new frontiers in the discovery of more fungal medicines.
“Fungi gave us penicillin,” says Sherry Gao, Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering (CBE) and in Bioengineering (BE) and senior author of a new paper in Nature Chemical Biology on the findings. “These results show that many more medicines derived from natural products remain to be found.”
From Curse to Cure
A. flavus, named for its yellow spores, has long been a microbial villain. After archaeologists opened King Tutankhamun’s tomb in the 1920s, a series of untimely deaths among the excavation team fuelled rumours of a pharaoh’s curse. Decades later, doctors theorised that fungal spores, dormant for millennia, could have played a role.
In the 1970s, a dozen scientists entered the tomb of Casimir IV in Poland. Within weeks, 10 of them died. Later investigations revealed the tomb contained A. flavus, whose toxins can lead to lung infections, especially in people with compromised immune systems.
Now, that same fungus is the unlikely source of a promising new cancer therapy.
A Rare Fungal Find
The therapy in question is a class of ribosomally synthesised and post-translationally modified peptides, or RiPPs, pronounced like the “rip” in a piece of fabric. The name refers to how the compound is produced – by the ribosome, a tiny cellular structure that makes proteins – and the fact that it is modified later, in this case, to enhance its cancer-killing properties.
“Purifying these chemicals is difficult,” says Qiuyue Nie, a postdoctoral fellow in CBE and the paper’s first author. While thousands of RiPPs have been identified in bacteria, only a handful have been found in fungi. In part, this is because past researchers misidentified fungal RiPPs as non-ribosomal peptides and had little understanding of how fungi created the molecules. “The synthesis of these compounds is complicated,” adds Nie. “But that’s also what gives them this remarkable bioactivity.”
Hunting for Chemicals
To find more fungal RiPPs, the researchers first scanned a dozen strains of Aspergillus, which previous research suggested might contain more of the chemicals.
By comparing chemicals produced by these strains with known RiPP building blocks, the researchers identified A. flavus as a promising candidate for further study.
Genetic analysis pointed to a particular protein in A. flavus as a source of fungal RiPPs. When the researchers turned the genes that create that protein off, the chemical markers indicating the presence of RiPPs also disappeared.
This novel approach – combining metabolic and genetic information – not only pinpointed the source of fungal RiPPs in A. flavus, but could be used to find more fungal RiPPs in the future.
A Potent New Medicine
After purifying four different RiPPs, the researchers found the molecules shared a unique structure of interlocking rings. The researchers named these molecules, which have never been previously described, after the fungus in which they were found: asperigimycins.
Even with no modification, when mixed with human cancer cells, asperigimycins demonstrated medical potential: two of the four variants had potent effects against leukaemia cells.
Another variant, to which the researchers added a lipid found in bees’ royal jelly, performed as well as cytarabine and daunorubicin, two FDA-approved drugs that have been used for decades to treat leukaemia.
Cracking the Code of Cell Entry
To understand why lipids enhanced asperigimycins’ potency, the researchers selectively turned genes on and off in the leukaemia cells. One gene, SLC46A3, proved critical in allowing asperigimycins to enter leukaemia cells in sufficient numbers.
That gene helps materials exit lysosomes, the tiny sacs that collect foreign materials entering human cells. “This gene acts like a gateway,” says Nie. “It doesn’t just help asperigimycins get into cells, it may also enable other ‘cyclic peptides’ to do the same.”
Like asperigimycins, those chemicals have medicinal properties – nearly two dozen cyclic peptides have received clinical approval since 2000 to treat diseases as varied as cancer and lupus – but many of them need modification to enter cells in sufficient quantities.
“Knowing that lipids can affect how this gene transports chemicals into cells gives us another tool for drug development,” says Nie.
Disrupting Cell Division
Through further experimentation, the researchers found that asperigimycins likely disrupt the process of cell division. “Cancer cells divide uncontrollably,” says Gao. “These compounds block the formation of microtubules, which are essential for cell division.”
Notably, the compounds had little to no effect on breast, liver or lung cancer cells – or a range of bacteria and fungi – suggesting that asperigimycins’ disruptive effects are specific to certain types of cells, a critical feature for any future medication.
Future Directions
In addition to demonstrating the medical potential of asperigimycins, the researchers identified similar clusters of genes in other fungi, suggesting that more fungal RiPPS remain to be discovered. “Even though only a few have been found, almost all of them have strong bioactivity,” says Nie. “This is an unexplored region with tremendous potential.”
The next step is to test asperigimycins in animal models, with the hope of one day moving to human clinical trials. “Nature has given us this incredible pharmacy,” says Gao. “It’s up to us to uncover its secrets. As engineers, we’re excited to keep exploring, learning from nature and using that knowledge to design better solutions.”
