Tag: Medication

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Molecular Atlas of Severe Preeclampsia Reveals New Therapeutic Targets

Researchers from University College London in England have created the most comprehensive molecular map to date of severe preeclampsia, uncovering distinct fetal and maternal drivers of the disease that could lead to more targeted therapies and earlier intervention.

The study, published in Science Advances, combined single-cell RNA sequencing with spatial transcriptomics across the entire fetal-maternal interface and found that severe preeclampsia is not solely a placental disorder. Instead, the disease involves coordinated dysfunction across multiple maternal and fetal tissues, with different molecular programs emerging in early- versus late-onset disease.

Preeclampsia affects 2% to 4% of pregnancies worldwide and remains a leading cause of maternal and fetal illness and death. Although it is traditionally viewed as a placental disease, the mechanisms responsible for widespread maternal inflammation and endothelial dysfunction have remained unclear.

To better define those mechanisms, investigators analyzed tissues from 20 pregnancies, including 10 women with severe preeclampsia and 10 gestational age-matched controls between 25 and 37 weeks of gestation. By matching pregnancies by gestational age rather than comparing preterm cases with healthy term pregnancies, the researchers were able to distinguish disease-related molecular changes from normal developmental differences.

The analysis revealed extensive placental abnormalities, including molecular signatures of hypoxia, angiogenic imbalance, fibrosis, and altered metabolism. The team also confirmed impaired invasion of fetal extravillous trophoblasts into the maternal uterus, a hallmark of preeclampsia that contributes to defective remodeling of maternal blood vessels.

Beyond the placenta, however, the study identified previously unrecognized maternal immune abnormalities extending into the myometrium and chorioamniotic membranes. These included widespread mitochondrial dysfunction, activation of type I interferon signaling, and altered macrophage responses, providing a potential explanation for the systemic inflammation and endothelial injury that characterize severe disease.

The findings point to several potential therapeutic targets. Leptin (LEP), which was strongly upregulated in placental cells throughout both early and late disease, may contribute to oxidative stress and vascular dysfunction. The researchers suggest that leptin antagonists, already under investigation for autoimmune diseases, warrant exploration as placental-targeted therapies.

The study also highlights type I interferon signaling as a promising target. Elevated interferon activity, detected in maternal immune cells and peripheral blood, could potentially serve as both a biomarker and a therapeutic target for anti-interferon or antioxidant treatments.

“IFN-I in peripheral blood promises better screening of patients that might benefit from anti-IFN or antioxidant therapeutics,” the authors concluded.

Perhaps most importantly, the molecular abnormalities were substantially more pronounced in early-onset disease, suggesting that intervention before clinical deterioration may offer the greatest benefit.

“Given the severity of molecular dysfunctions in early disease, compared to its late presentation, timely intervention during gestation is likely beneficial and could change the extremely poor prognosis of severe PE,” the authors wrote.

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Gut Bacteria Chemical Linked to Irregular Heart Beat

A chemical called trimethylamine N-oxide (TMAO), which originates from gut bacteria digesting animal products such as red meat, is present at higher levels in the blood of people with an irregular heart beat than the rest of the population.

The researchers found that after they had controlled for various factors like age and comorbidities, people in the top third of TMAO levels had a 70% increased risk of having atrial fibrillation compared with those in the bottom third.

Atrial fibrillation is the most common sustained heart rhythm disorder in the U.S. impacting more than 10 million adults. It occurs because the upper chambers of the heart beat rapidly and irregularly, which can lead to blood clots, stroke and heart failure if left unchecked.

TMAO is formed when trimethylamine produced by gut bacteria is carried to the liver and oxidized. Animal-derived foods such as red and processed meat, eggs, high fat dairy products, and some supplements, are the main dietary precursors for production of TMAO. It has previously been linked to increased risk of cardiovascular disease more generally, but whether high levels of this chemical increased risk of atrial fibrillation was less clear.

In this study, published in the journal of Journal of Clinical Investigation, lead investigator Robert Koeth, MD, PhD, a clinician scientist based at the Cleveland Clinic, and colleagues assessed blood TMAO levels in 5,000 adults who underwent elective heart catheterization for known or suspected cardiovascular disease.

They also studied the effects of TMAO on heart beat regularity in model mice susceptible to atrial fibrillation and tested a potential candidate drug to see if it could reduce levels of TMAO in these animals.

After controlling for age, sex, diabetes, cardiovascular disease, blood pressure, smoking, body mass index, inflammation and kidney function, people with the highest TMAO levels had about 1.7‑times the odds of having atrial fibrillation compared with people with the lowest levels.

In the mouse studies, when TMAO levels in the blood were higher, the animals developed atrial fibrillation sooner and it became a persistent problem more quickly. The researchers also saw changes in how electrical signals moved through parts of the heart that made it easier for abnormal rhythms to start and continue.

The researchers tested iodomethylcholine in the mice, an experimental small molecule drug that blocks the gut microbial enzyme responsible for converting choline into trimethylamine. In response to the drug, TMAO levels fell, the mix of gut bacteria changed, and both the first episodes of atrial fibrillation and its progression were delayed without notable negative effects on the liver.

“A possible pathogenic culprit for the development of atrial myopathy and electromechanical dysfunction is chronic autonomic dysfunction from TMAO inhibition of the M2 muscarinic acetylcholine receptor and increasing sympathetic tone,” write Koeth and team.

The results suggest “TMAO promotes atrial fibrillation in a gut microbiota dependent manner by causing autonomic dysfunction, atrial myopathy, and electromechanical dysfunction,” they conclude.

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Dual Bispecific Regimen Shows Strong Phase III Signal in Earlier-Line Relapsed Myeloma

Bispecific antibodies are moving rapidly from late-line rescue therapy into earlier phases of multiple myeloma care. The latest signal comes from MonumenTAL-6, a Phase III study evaluating Johnson & Johnson’s TECVAYLI® (teclistamab) plus TALVEY® (talquetamab) in patients with relapsed or refractory multiple myeloma who had received one to four prior lines of therapy, including an anti-CD38 antibody and lenalidomide.

According to topline results released by the company, the dual bispecific regimen reduced the risk of disease progression or death by 89% compared with investigator’s choice standard of care, corresponding to a hazard ratio of 0.11. The combination also reduced the risk of death by 62%, with a hazard ratio of 0.38. A second investigational arm, TALVEY plus pomalidomide, also met the primary endpoint, reducing the risk of progression or death by 73%.

A dual-antigen strategy

The clinical rationale is clear. TECVAYLI targets BCMA, a validated plasma cell antigen, while TALVEY targets GPRC5D, another antigen highly expressed on myeloma cells. Combining the two agents could deepen tumor control by engaging T cells against two distinct myeloma-associated targets, potentially reducing the likelihood that disease escapes through antigen loss or heterogeneous target expression.

This dual-antigen approach is particularly relevant in earlier-line relapse, where patients may still have better marrow reserve, less heavily treated immune systems, and more opportunity to achieve durable disease control. It also reflects a broader shift in myeloma treatment: immunotherapy is no longer being reserved only for patients who have exhausted conventional options.

“These findings add to a growing body of Phase III evidence evaluating the survival outcomes associated with the early use of immunotherapy doublets in the treatment journey,” said Ajay K. Nooka, MD, MPH, director of the Myeloma Program at Emory University School of Medicine.

Topline data, not yet full clinical detail

MonumenTAL-6 compared TECVAYLI plus TALVEY and TALVEY plus pomalidomide with investigator’s choice of elotuzumab, pomalidomide and dexamethasone or pomalidomide, bortezomib and dexamethasone. The Independent Data Monitoring Committee recommended unblinding the study at the first interim analysis, and Johnson & Johnson said full data will be presented at a future medical meeting and submitted to global regulatory authorities.

That timing matters. The reported hazard ratios are striking, particularly for progression-free survival with the TECVAYLI-TALVEY arm. However, clinicians will need the full dataset to assess response depth, duration, subgroup consistency, treatment discontinuation, infection burden, cytopenias, quality-of-life effects, and practical feasibility in community settings.

Safety will be central to interpretation. Both drugs are T-cell redirecting bispecific antibodies and carry risks including cytokine release syndrome, neurologic toxicity including ICANS, infections, cytopenias, and other target-specific adverse events. The company reported that overall safety profiles in MonumenTAL-6 were consistent with the known profiles of the individual monotherapies, but detailed rates from the combination study have not yet been released.

Implications for myeloma sequencing

If confirmed, these data could strengthen the case for earlier use of off-the-shelf bispecific combinations in relapsed myeloma. TECVAYLI is already approved in combination with daratumumab and hyaluronidase in certain patients after at least one prior line of therapy, while TALVEY is currently approved as monotherapy for more heavily pretreated relapsed or refractory disease.

The key question is no longer only whether bispecific antibodies work, but how they should be sequenced and combined alongside CD38 antibodies, proteasome inhibitors, immunomodulatory drugs, CAR T therapies, and emerging antibody-drug conjugates. A BCMA/GPRC5D combination may offer a way to intensify immune pressure without the manufacturing delays associated with autologous cell therapy, but it will also require careful infection prevention, monitoring infrastructure, and patient selection.

For now, MonumenTAL-6 adds an important signal to the changing treatment landscape. Earlier-line myeloma therapy is becoming increasingly immunotherapy-based, and dual-antigen targeting may become one of the strategies used to push responses deeper and make remission more durable.

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STAT+: Merck strikes voluntary licensing deals in poor countries for an experimental HIV prevention pill

Amid rising concern over efforts to contain HIV, Merck has reached voluntary licensing deals with seven companies to make generic versions of an experimental, once-a-month prevention pill in 129 low- and middle-income countries.

The agreements will allow the manufacturers — three of which are based in Africa and four in India — to sell generic versions to both public and private buyers, which is designed to ensure the medicine becomes available to the widest possible population. Moreover, the deals are royalty free, which makes it easier for the generic companies to predict costs.

The timing of the announcement is notable because Merck is striking these deals while its medicine, known as alimatravir, is currently undergoing a pair of late-stage clinical trials. By doing so now, the company believes it will help the generic makers plan for wide-scale production and the necessary steps to receive regulatory approvals around the world.

Continue to STAT+ to read the full story…

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Drug Candidate Combats Age-Related Muscle Loss

Researchers in Japan have identified a compound that could help muscles stay strong as we age. Preclinical results published today in Scientific Reports uncover a promising new approach to treat conditions causing muscle loss and may help people preserve independence and quality of life in their later years. 

Skeletal muscle is essential for movement, accounting for approximately 40% of an adult’s total body weight. Yet it is also one of the first tissues to decline with age, progressively leading to weakness, scarring, fat accumulation, and loss of fast-twitch muscle fibers.

The study focused on hepatocyte growth factor (HGF), a molecule that plays a crucial role in activating the repair of muscle fibers. In healthy muscle, this molecule is present in the tissue surrounding muscle fibers. When the muscle is injured or stimulated through exercise, HGF is released and binds to c-met receptors on stem cells within the skeletal muscle, known as satellite cells. This activates the satellite cells and enables them to proliferate and differentiate to repair muscle fibers. 

Aging can interfere with this process, making it a key driver of age-related muscle wasting. In an earlier study, the same team found that aging causes HGF to undergo nitration, a chemical modification that prevents it from binding to c-met receptors.

“HGF is not necessarily missing as we age,” said Ryuichi Tatsumi, PhD, professor at Kyushu University. “Rather, it can be chemically altered after it is made. That led us to wonder whether a compound with strong antioxidant capacity might protect HGF, either by preventing nitration or by compensating for the functional loss it causes.”

Tatsumi’s team then identified two compounds with strong antioxidant activity that could potentially interfere with HGF nitration: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS). Both belong to a drug class known as trisulfides that has been gaining attention in preclinical research for their protective and anti-inflammatory properties across a wide range of indications. 

While both drugs were able to suppress HGF nitration, only LASSS restored its ability to bind to c-met receptors. In fact, the drug candidate more than doubled HGF’s binding affinity while simultaneously preventing nitration. 

“This exceeded our expectations,” said Tatsumi. “We knew trisulfides had diverse biological functions, but we never expected that simply mixing HGF with LASSS would produce such a striking effect. What this tells us is that LASSS does more than simply neutralize reactive molecules. It may interact directly with HGF and induce a subtle structural change, creating an enhanced ‘Super HGF’ form that binds c-met more strongly and resists nitration.”

The researchers then tested these effects in a mouse model of muscle atrophy. Compared to untreated animals, mice receiving LASSS showed a significant reduction in HGF nitration. Although further preclinical studies are needed before this approach can be tested in humans, these early findings point toward a promising strategy to preserve the muscle’s natural regenerative capacity and support healthy aging. 

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Early detection of Alzheimer’s disease with circular RNA from blood

Nature Medicine, Published online: 23 July 2026; doi:10.1038/s41591-026-04563-8

Early diagnosis of Alzheimer’s disease is important to ensure timely and accurate treatment. We show that a blood-based circular RNA signature can accurately detect Alzheimer’s disease as well as, or better than, current biomarkers and even predict who will develop symptoms before they appear. This less invasive approach could offer earlier diagnosis and improved monitoring of Alzheimer’s disease.

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Type 1 Diabetes-Induced Kidney Disease Treated with Phase III Trial Drug

Those living with type 1 diabetes not only face the challenges of living with a chronic illness, but they also contend with the potential of developing secondary conditions, including kidney disease. Nearly a third of patients with type 1 diabetes develop kidney disease, resulting in diabetes as the leading cause of kidney disease worldwide. With such a broad impact, and few approved therapies, research into therapeutic strategies to help patients prevent or recover from diabetes-induced chronic kidney disease is much needed.

Research on type 2 diabetes suggests that inhibitors against the SGLT2 protein improve function and reduce damage to kidneys. Thought the mechanism behind this protective effect remains unclear, an SGLT2 inhibitor, dapagliflozin, has shown success in clinical trials led by Petter Bjornstad, MD, physician-scientist and executive director of the University of Washington Medicine Diabetes Institute.

Bjornstad & colleagues have developed their clinical trial to assess the effects of dapagliflozin in adolescents. Their new paper published in Science Translational Medicine shows the results of a section of their phase III data from the Adolescent Type 1 Diabetes Treatment With SGLT2i for hyperglycEMia & hyPerfilTration (ATTEMPT) trial.

The authors described this analysis of the broader trial as “a multimodal view of how the kidney of a person with T1D responds to SGLT2 inhibition.”

Data from 98 children aged 12 to 21, was analyzed to detail the effects of dapagliflozin in combination with insulin therapy on kidney function and physiology. Participants in both a placebo-control group and the treatment group were treated for 16 weeks, then underwent “sequential kidney biopsies, multiparametric kidney MRI, and plasma/urine proteomics,” though biopsies were only carried out in patients over 18 years of age.

Molecular profiles of the serialized biopsies showed a reversal of molecular hallmarks including transcriptional shifts using single-cell RNA seq, downregulation of glycolysis, gluconeogenesis, and oxidative stress markers, and reduced inflammatory gene expression.

“These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation,” the authors wrote.

Analysis of proteomics in urine samples showed similar results. The tissue changes included decreased injury markers and increased numbers of protective proteins, suggesting that dapagliflozin has a reversing effect on diabetes-induced kidney damage.

“Cross-cohort comparison against healthy controls showed that over 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns,” indicated the authors.

Not only were kidney markers improved in treated patients, but these patients also showed overall improvement including improved blood sugar control and more normal kidney function.

“Because adjunctive SGLT2 inhibition is considered for people with T1D in the future, our results offer mechanistic reassurance that the drug engages kidney-protective pathways similar to those in type 2 diabetes,” they wrote.

In addition to determining the mechanistic impacts of dapagliflozin in kidney disease using a subset of data from a clinical trial, the authors point out that this work has a broader impact for other clinical trials with multiple data streams.

“Our study showcases the power of deep phenotyping in clinical trials to elucidate drug mechanisms in vivo,” they point out.

“Ultimately, combining rigorous clinical trials with translational science approaches will accelerate the development of therapies to reduce the burden of DKD in T1D,” concluded the authors.

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