In a new study, researchers found that a new drug under development, zerlasiran, depleted levels of lipoprotein(a) by more than 80% in participants with increased cardiovascular risk. The drug was well tolerated and the findings, published in JAMA Network, suggest that this could be the first viable treatment for elevated levels of lipoprotein(a).
Elevated levels of lipoprotein(a) (LPa) – a type of cholesterol – is a genetic risk factor for cardiovascular disease. Present in 20% of the population, it increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Currently, there are no interventions which can bring down high LPa levels: it is unresponsive to diet, exercise, and other lifestyle changes and there is no available drug.
Zerlasiran, a small-interfering RNA that targets synthesis of LPa serum concentration, was developed to fill this gap. It is effectively a gene silencer that shuts down LPA, a gene which produces a protein found only in LPa. This in turn is expected to reduce cardiovascular risk.
A phase I clinical trial had shown that zerlasiran was safe and effective.
For the study, researchers enrolled 178 patients (average age 63.7 years, 46 female) with ASCVD and LPa concentrations greater than or equal to 125nmol/L. They were randomised to subcutaneously receive zerlasiran 300mg or 450mg, or a placebo, every 16 or every 24 weeks. The least-squares mean placebo-adjusted time-averaged percent change in LPa serum concentrations was −85.6%, −82.8%, and −81.3% for the 450mg every 24 weeks, 300mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. The most common adverse events were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug. For the group receiving a 300mcg dose every 16 weeks, it was found that even at the 60 week follow-up, 28 weeks after the last administration, that lipoprotein(a) serum concentrations were still 60% lower than baseline.
Left: Normal cervical cancer cells with well-formed nuclei in blue and elongated actin filaments – which play an essential role in cell survival and division – in green. Right: Destabilised cervical cancer cells after gold compound treatment show structural integrity compromised while the nuclei in blue are breaking apart, indicating cell death. Credit: RMIT University
Gold-based drugs can slow tumour growth in animals by 82% and target cancers more selectively than standard chemotherapy drugs, according to new research out of RMIT University. The study published in the European Journal of Medicinal Chemistry reveals a new gold-based compound that’s 27 times more potent against cervical cancer cells in the lab than standard chemotherapy drug cisplatin.
It was also 3.5 times more effective against prostate cancer and 7.5 times more effective against fibrosarcoma cells in the lab. In mice studies, the gold compound reduced cervical cancer tumour growth by 82%, compared to cisplatin’s 29%.
Project lead at RMIT, Distinguished Professor Suresh Bhargava AM, said it marked a promising step towards alternatives to platinum-based cancer drugs.
“These newly synthesised compounds demonstrate remarkable anticancer potential, outperforming current treatments in a number of significant aspects including their selectivity in targeting cancer cells,” said Bhargava, Director of RMIT’s Centre for Advanced Materials and Industrial Chemistry. “While human trials are still a way off, we are really encouraged by these results.”
The gold-based compound is patented and ready for further development towards potential clinical application.
Gold: the noblest element
Photo by Jingming Pan on Unsplash
Gold is famously known as the noblest of all metals because it has little or no reaction when encountering other substances. However, the gold compound used in this study is a chemically tailored form known as Gold(I), designed to be highly reactive and biologically active.
This chemically reactive form was then tailored to interact with an enzyme abundant in cancer cells, known as thioredoxin reductase.
By blocking this protein’s activity, the gold compound effectively shuts down cancer cells before they can multiply or develop drug resistance.
Project co-lead at RMIT, Distinguished Professor Magdalena Plebanski, said along with this ability to block protein activity, the compound also had another weapon in its anti-cancer arsenal.
In zebrafish studies, it was shown to stop the formation of new blood vessels that tumours need in order to grow.
This was the first time one of the team’s various gold compounds had shown this effect, known as anti-angiogenesis.
The drug’s effectiveness at using these two attacks simultaneously was demonstrated against a range of cancer cells.
This included ovarian cancer cells, which are known to develop resistance to cisplatin treatment in many cases.
“Drug resistance is a significant challenge in cancer therapy,” said Plebanski, who heads RMIT’s Cancer, Ageing, and Vaccines Laboratory.
“Seeing our gold compound have such strong efficacy against tough-to-treat ovarian cancer cells is an important step toward addressing recurrent cancers and metastases.”
Gold has been a cornerstone of Indian Ayurvedic treatments for centuries, celebrated for its healing properties. Today, gold-based cancer treatments are gaining global traction, with advancements such as the repurposing of the anti-arthritic drug auranofin, now showing promise in clinical trials for oncology.
“We know that gold is readily accepted by the human body, and we know it has been used for thousands of years in treating various conditions,” Bhargava said.
“Essentially, gold has been market tested, but not scientifically validated.
“Our work is helping both provide the evidence base that’s missing, as well as delivering new families of molecules that are tailor-made to amplify the natural healing properties of gold,” he said.
Bhargava said this highly targeted approach minimises the toxic side effects seen with the platinum-based cisplatin, which targets DNA and damages both healthy and cancerous cells.
“Their selectivity in targeting cancer cells, combined with reduced systemic toxicity, points to a future where treatments are more effective and far less harmful,” Bhargava said.
This specific form of gold was also shown to be more stable than those used in earlier studies, allowing the compound to remain intact while reaching the tumour site.
Scientists at UCLA have developed a first-of-its-kind experimental therapy that has the potential to enhance heart repair following a heart attack, preventing the onset of heart failure. After a heart attack, the heart’s innate ability to regenerate is limited, causing the muscle to develop scars to maintain its structural integrity. This inflexible scar tissue, however, interferes with the heart’s ability to pump blood, leading to heart failure in many patients – 50% of whom do not survive beyond five years.
The new therapeutic approach aims to improve heart function after a heart attack by blocking a protein called ENPP1, which is responsible for increasing the inflammation and scar tissue formation that exacerbate heart damage. The findings, published in Cell Reports Medicine, could represent a major advance in post-heart attack treatment.
The research was led by senior author Dr Arjun Deb, a professor of medicine and molecular, cell and developmental biology at UCLA.
“Despite the prevalence of heart attacks, therapeutic options have stagnated over the last few decades,” said Deb, who is also a member of the UCLA Broad Stem Cell Research Center. “There are currently no medications specifically designed to make the heart heal or repair better after a heart attack.”
The experimental therapy uses a therapeutic monoclonal antibody engineered by Deb and his team. This targeted drug therapy is designed to mimic human antibodies and inhibit the activity of ENPP1, which Deb had previously established increases in the aftermath of a heart attack.
The researchers found that a single dose of the antibody significantly enhanced heart repair in mice, preventing extensive tissue damage, reducing scar tissue formation and improving cardiac function. Four weeks after a simulated heart attack, only 5% of animals that received the antibody developed severe heart failure, compared with 52% of animals in the control group.
This therapeutic approach could become the first to directly enhance tissue repair in the heart following a heart attack; an advantage over current therapies that focus on preventing further damage but not actively promoting healing. This can be attributed to the way the antibody is designed to target cellular cross-talk, benefitting multiple cell types in the heart, including heart muscle cells, the endothelial cells that form blood vessels, and fibroblasts, which contribute to scar formation.
Initial findings from preclinical studies also show that the antibody therapy safely decreased scar tissue formation without increasing the risk of heart rupture – a common concern after a heart attack. However, Deb acknowledges that more work is needed to understand potential long-term effects of inhibiting ENPP1, including potential adverse effects on bone mass or bone calcification.
Deb’s team is now preparing to move this therapy into clinical trials. The team plans to submit an Investigational New Drug, or IND, application to the U.S. Food and Drug Administration this winter with the goal of beginning first-in-human studies in early 2025. These studies will be designed to administer a single dose of the drug in eligible individuals soon after a heart attack, helping the heart repair itself in the critical initial days after the cardiac event.
While the current focus is on heart repair after heart attacks, Deb’s team is also exploring the potential for this therapy to aid in the repair of other vital organs.
“The mechanisms of tissue repair are broadly conserved across organs, so we are examining how this therapeutic might help in other instances of tissue injury,” said Deb, who is also the director of the UCLA Cardiovascular Research Theme at the David Geffen School of Medicine. “Based on its effect on heart repair, this could represent a new class of tissue repair-enhancing drugs.”
While toxic in high concentrations, copper is essential to life as a trace element. Many tumours require significantly more copper than healthy cells for growth – something which new cancer treatments might exploit this. In the journal Angewandte Chemie, a research team from the Max Planck Institute for Polymer Research has now introduced a novel method by which copper is effectively removed from tumours cells, killing them.
Copper is an essential cofactor for a variety of enzymes that play a role in the growth and development of cells. For example, copper ions are involved in antioxidant defence. Cells very strictly regulate the concentration and availability of copper ions. On the one hand, enough copper ions must be on hand; on the other, the concentration of free copper ions in the cytoplasm must be kept very low to avoid undesired side effects. Extracellular, doubly charged copper ions are reduced to singly charged copper, transported into the cell, stored in pools, and transferred to the biomolecules that require them on demand. To maintain the cellular copper equilibrium (homeostasis), cells have developed clever trafficking systems that use a variety of transporters, ligands, chaperones (proteins that help other complex proteins to fold correctly), and co-chaperones.
Because cancer cells grow and multiply much more rapidly, they have a significantly higher need for copper ions. Restricting their access to copper ions could be a new therapeutic approach. The problem is that it has so far not been possible to develop drugs that bind copper ions with sufficient affinity to “take them away” from copper-binding biomolecules.
In cooperation with the Stanford University School of Medicine (Stanford/CA, USA) and Goethe University Frankfurt/Main (Germany), Tanja Weil, Director of the Max Planck Institute for Polymer Research (Mainz) and her team have now successfully developed such a system. At the heart of their system are the copper-binding domains of the chaperone Atox1. The team attached a component to this peptide that promotes its uptake into tumour cells. An additional component ensures that the individual peptide molecules aggregate into nanofibres once they are inside the tumour cells. In this form, the fibre surfaces have many copper-binding sites in the right spatial orientation to be able to grasp copper ions from three sides with thiol groups (chelate complex). The affinity of these nanofibres for copper is so high that they also grab onto copper ions in the presence of copper-binding biomolecules. This drains the copper pools in the cells and deactivates the biomolecules that require copper. As a consequence, the redox equilibrium of the tumour cell is disturbed, leading to an increase in oxidative stress, which kills the tumour cell. In experiments carried out on cell cultures under special conditions, over 85% of a breast cancer cell culture died off after 72 hours while no cytotoxicity was observed for a healthy cell culture.
The research team hopes that some years in the future, these fundamental experiments will perhaps result in the development of useful methods for treating cancer.
Researchers at the University of Vienna develop gut-stable oxytocin analogues for targeted pain treatment of chronic abdominal pain
Photo by Andrea Piacquadio on Pexels
A research team at the University of Vienna, led by medicinal chemist Markus Muttenthaler, has developed a new class of oral peptide therapeutic leads for treating chronic abdominal pain. This groundbreaking innovation offers a safe, non-opioid-based solution for conditions such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD), which affect millions of people worldwide. The research results were published in Angewandte Chemie.
An innovative approach to pain management
Current medications used to treat chronic abdominal pain often rely on opioids. However, opioids can cause severe side effects such as addiction, nausea, and constipation. Additionally, they affect the central nervous system, often leading to fatigue and drowsiness, which impairs the quality of life of those affected. The addiction risk is particularly problematic and has contributed to the ongoing global opioid crisis. Therefore, there is an urgent need for alternatives that minimise these risks.
This new therapeutic approach targets oxytocin receptors in the gut, which, in addition to its role in social bonding, also affects pain perception. When the peptide hormone oxytocin binds to these receptors, it triggers a signal that reduces pain signals in the gut. The advantage of this approach is that the effect is gut-specific, thus having a lower risk of side effects due to its non-systemic, gut-restricted action.
Oxytocin itself cannot be taken orally because it is rapidly broken down in the gastrointestinal tract. However, Prof Muttenthaler’s team has successfully created oxytocin compounds that are fully gut-stable yet can still potently and selectively activate the oxytocin receptor. This means these newly developed oxytocin-like peptides can be taken orally, allowing for convenient treatment for patients. This approach is especially innovative since most peptide drugs (such as insulin, GLP1 analogues) need to be injected as they are also quickly degraded in the gut.
“Our research highlights the therapeutic potential of gut-specific peptides and offers a new, safe alternative to existing pain medications, particularly for those suffering from chronic gut disorders and abdominal pain,” explains Muttenthaler.
Next steps and future outlook
With support from the European Research Council, the scientists are now working to translate their research findings into practice. The goal is to bring these new peptides to market as an effective and safe treatment for chronic abdominal pain. Moreover, the general approach of oral, stable, and gut-specific peptide therapeutics could revolutionise the treatment of gastrointestinal diseases, as the therapeutic potential of peptides in this area has not yet been fully explored.
The team has already secured a patent for the developed drug leads and is now actively seeking investors and industrial partners to advance the drug leads towards the clinic.
Human colon cancer cells. Credit: National Cancer Institute
Tumours often contain areas of oxygen-deficient tissue that frequently withstand conventional therapies. This is because the drugs applied in tumours require oxygen to be effective. An international research team has developed a novel mechanism of action that works without oxygen: polymeric incorporated nanocatalysts target the tumour tissue selectively and switch off the glutathione that the cells need to survive. The team published their findings in the journal Nature Communications.
Why tumours shrink but don’t disappear
Study leader Dr Johannes Karges from Ruhr University Bochum, Germany, explained: “As tumours grow very quickly, consume a lot of oxygen and their vascular growth can’t necessarily keep pace, they often contain areas that are poorly supplied with oxygen.” These areas, often in the centre of the tumour, frequently survive treatment with conventional drugs, so that the tumour initially shrinks but doesn’t disappear completely. This is because the therapeutic agents require oxygen to be effective.
The mechanism of action developed by Karges’ team works without oxygen. “It’s a catalyst based on the element ruthenium, which oxidises the naturally present glutathione in the cancer cells and switches it off,” explains Karges. Glutathione is essential for the survival of cells and protects them from a wide range of different factors. If it ceases to be effective, the cell deteriorates.
Compound accumulates in tumour tissue
All cells of the body need and contain glutathione. However, the catalyst has a selective effect on cancer cells as it is packaged in polymeric nanoparticles that accumulate specifically in the tumour tissue. Experiments on cancer cells and on mice with human tumours, that were considered incurable, proved successful. “These are encouraging results that need to be confirmed in further studies,” concludes Johannes Karges. “Still, there’s a lot of research work to be done before it can be used in humans.”
Plant fungus provides new drug with a new cellular target
Human colon cancer cells. Credit: National Cancer Institute
Novel chemical compounds from a fungus could provide new perspectives for treating colorectal cancer, one of the most common and deadliest cancers worldwide. The fungus, Bipolaris victoriae, is otherwise known as a fungal plant pathogen which in the 1940s caused the “Victoria blight”, decimating oats and similar grains in the US.
In the journal Angewandte Chemie, researchers reported on the isolation and characterisation of a previously unknown class of metabolites (terpene-nonadride heterodimers). One of these compounds effectively kills colorectal cancer cells by attacking the enzyme DCTPP1, which thus may serve as a potential biomarker for colorectal cancer and a therapeutic target.
Rather than using conventional cytostatic drugs, which have many side effects, modern cancer treatment frequently involves targeted tumour therapies directed at specific target molecules in the tumour cells. The prognosis for colorectal cancer patients remains grim however, demanding new targets and novel drugs.
Targeted tumour therapies are mostly based on small molecules from plants, fungi, bacteria, and marine organisms. About half of current cancer medications were developed from natural substances. A team led by Ninghua Tan, Yi Ma, and Zhe Wang at the China Pharmaceutical University (Nanjing, China) chose to use Bipolaris victoriae S27, a fungus that lives on plants, as the starting point in their search for new drugs.
The team first analysed metabolic products by cultivating the fungus under many different conditions (OSMAC method, one strain, many compounds). They discovered twelve unusual chemical structures belonging to a previously unknown class of compounds: terpene-nonadride heterodimers, molecules made from one terpene and one nonadride unit. Widely found in nature, terpenes are a large group of compounds with very varied carbon frameworks based on isoprene units. Nonadrides are nine-membered carbon rings with maleic anhydride groups. The monomers making up this class of dimers termed “bipoterprides” were also identified and were found to contain additional structural novelties (bicyclic 5/6-nonadrides with carbon rearrangements).
Nine of the bipoterprides were effective against colorectal cancer cells. The most effective was bipoterpride No. 2, which killed tumour cells as effectively as the classic cytostatic drug Cisplatin. In mouse models, it caused tumours to shrink with no toxic side effects.
The team used a variety of methods to analyse the drug’s mechanism: bipoterpride 2 inhibits dCTP-pyrophosphatase 1 (DCTPP1), an enzyme that regulates the cellular nucleotide pool. The heterodimer binds significantly more tightly than each of its individual monomers. The activity of DCTPP1 is elevated in certain types of tumours, promoting the invasion, migration, and proliferation of the cancer cells while also inhibiting programmed cell death. It can also help cancer cells to resist treatment. Bipoterpride 2 inhibits this enzymatic activity and disrupts the now pathologically altered amino acid metabolism in the tumour cells.
The team was thus able to identify DCTPP1 as a new target for the treatment of colorectal cancer and bipoterprides as new potential drug candidates.
Scientists at Trinity College Dublin have discovered a new process in the immune system that leads to the production of an important family of anti-viral proteins called interferons. They hope the discovery will now lead to new, effective therapies for people with some autoimmune and infectious diseases.
Reporting in Nature Metabolism, Luke O’Neill, Professor of Biochemistry in the School of Biochemistry and Immunology at Trinity, and his team have found that a natural metabolite called Itaconate can stimulate immune cells to make interferons by blocking an enzyme called SDH.
Co-lead author, Shane O’Carroll, from Trinity’s School of Biochemistry and Immunology, said: “We have linked the enzyme SDH to the production of interferons in an immune cell type called the macrophage. We hope our work will help the effort to develop better strategies to fight viruses because interferons are major players in how our innate immune system eliminates viruses – including COVID-19.”
Co-lead author, Christian Peace, from Trinity’s School of Biochemistry and Immunology, added: “Itaconate is a fascinating molecule made by macrophages during infections. It’s already known to suppress damaging inflammation but now we have found how it promotes anti-viral interferons.”
Working with drug companies Eli Lilly and Sitryx Ltd, the next step is to test new therapies based on Itaconate in various diseases, with some autoimmune diseases and some infectious diseases on the likely list. And the work potentially extends to other disease contexts in which SDH is inhibited, such as cancer, and could reveal a new therapeutic target for SDH-deficient tumours.
Prof O’Neill said: “With Itaconate you get two for the price of one – not only can it block harmful inflammation, but it can also help fight infections. We have discovered important mechanisms for both and the hope now is that patients will benefit from new therapies that exploit Itaconate and its impacts.”
Clinical trials in patients are set to start next year.
Bioactive glasses, a filling material which can bond to tissue and improve the strength of bones and teeth, has been combined with gallium to create a potential treatment for bone cancer. Tests in labs have found that bioactive glasses doped with the metal have a 99% success rate of eliminating cancerous cells and can even regenerate diseased bones.
In laboratory tests 99% of osteosarcoma (bone cancer) cells were killed off without destroying non-cancerous normal human bone cells. The researchers also incubated the bioactive glasses in a simulated body fluid and after seven days they detected the early stages of bone formation.
Gallium is highly toxic, and the researchers found that the ‘greedy’ cancer cells soak it up and self-kill, which prevented the healthy cells from being affected. Their research appears in the journal Biomedical Materials.
Osteosarcoma is the mostly commonly occurring primary bone cancer and despite the use of chemotherapy and surgery to remove tumours survival rates have not improved much since the 1970s. Survival rates are dramatically reduced for patients who have a recurrence and primary bone cancer patients are more susceptible to bone fractures.
Despite extensive research on different types of bioactive glass or ceramics for bone tissue engineering, there is limited research on targeted and controlled release of anti-cancer agents to treat bone cancers.
Professor Martin said: “There is an urgent need for improved treatment options and our experiments show significant potential for use in bone cancer applications as part of a multimodal treatment.
“We believe that our findings could lead to a treatment that is more effective and localised, reducing side effects, and can even regenerate diseased bones.
“When we observed the glasses, we could see the formation of a layer of amorphous calcium phosphate/ hydroxy apatite layer on the surface of the bioactive glass particulates, which indicates bone growth.” The glasses were created in the Aston University labs by rapidly cooling very high temperature molten liquids (1450°C) to form glass. The glasses were then ground and sieved into tiny particles which can then be used for treatment.
In previous research the team achieved a 50% success rate but although impressive, this was not enough to be a potential treatment. The team are now hoping to attract more research funding to conduct trials using gallium.
Dr Lucas Souza, research laboratory manager for the Dubrowsky Regenerative Medicine Laboratory at the Royal Orthopaedic Hospital, Birmingham worked on the research with Professor Martin. He added: “The safety and effectiveness of these biomaterials will need to be tested further, but the initial results are really promising.
“Treatments for a bone cancer diagnosis remain very limited and there’s still much we don’t understand. Research like this is vital to support in the development of new drugs and new methodologies for treatment options.”
Four plants eaten by gorillas, also used in Gabonese traditional medicine, have antibacterial effects
Four plants consumed by wild gorillas in Gabon and used by local communities in traditional medicine show antibacterial and antioxidant properties, find Leresche Even Doneilly Oyaba Yinda from the Interdisciplinary Medical Research Center of Franceville in Gabon and colleagues in a new study publishing September 11 in the open-access journal PLOS ONE.
Wild great apes often consume medicinal plants that can treat their ailments. The same plants are often used by local people in traditional medicine.
To investigate, researchers observed the behavior of western lowland gorillas (Gorilla gorilla gorilla) in Moukalaba-Doudou National Park in Gabon and recorded the plants they ate. Next, they interviewed 27 people living in the nearby village of Doussala, including traditional healers and herbalists, about the plants that were used in local traditional medicine. The team identified four native plant species that are both consumed by gorillas and used in traditional medicine: the fromager tree (Ceiba pentandra), giant yellow mulberry (Myrianthus arboreus), African teak (Milicia excelsa) and fig trees (Ficus). They tested bark samples of each plant for antibacterial and antioxidant properties and investigated their chemical composition.
The researchers found that the bark of all four plants had antibacterial activity against at least one multidrug-resistant strain of the bacterium Escherichia coli. The fromager tree showed “remarkable activity” against all tested E. coli strains. All four plants contained compounds that have medicinal effects, including phenols, alkaloids, flavonoids, and proanthocyanidins. However, it’s not clear if gorillas consume these plants for medicinal or other reasons.
Biodiverse regions, such as central Africa, are home to a huge reservoir of unexplored and potentially medicinal plants. This research provides preliminary insights about plants with antibacterial and antimicrobial properties, and the four plants investigated in this study might be promising targets for further drug discovery research – particularly with the aim of treating multidrug-resistant bacterial infections.
The authors add: “Alternative medicines and therapies offer definite hope for the resolution of many present and future public health problems. Zoopharmacognosy is one of these new approaches, aimed at discovering new drugs.”
