Psoriasis is a chronic inflammatory skin disease that affects more than 60 million people worldwide, leaving them with uncomfortable rashes, itching, and anxiety. Treatments have advanced from topical and phototherapy to biologics targeting inflammatory cytokines. However, biologics often carry risks such as viral infections, tuberculosis, and malignancy and fail in as many as 38% of patients.

“These limitations demand alternative treatments targeting underlying pathogenic mechanisms,” write Fei Li (Xi’an Jiaotong University, China) and co-authors in Science Translational Medicine.

In their search for potential alternatives, Li and team investigated the role of CHI3L2, which has previously been identified as a shared core susceptibility gene between psoriasis and inflammatory bowel disease.

First, they found that CHI3L2 levels were elevated in serum and lesional skin samples from patients with psoriasis, and that levels were higher in patients with more severe disease.

To investigate the molecular pathways behind this, the investigators measured CHI3L2 levels in preclinical models of psoriasis. They showed that the protein is predominantly expressed in keratinocytes within psoriatic skin lesions and is up-regulated in response to inflammatory stimuli. Within the keratinocytes, CHI3L2 triggers a self-regulatory inflammatory loop via induction of cytokines, chemokines, and receptors.

Li and team then developed neutralizing antibodies specifically against CHI3L2, which not only suppressed inflammatory responses and proliferation of keratinocytes but also reduced skin inflammation in the preclinical model.

“In pathological and serological evaluations, these antibodies yielded efficacy comparable to those of anti–IL-17 and anti–TNF-α agents,” Li et al. remark.

Furthermore, they showed that CHI3L2 is pathologically induced specifically in keratinocytes within psoriatic lesions, meaning that targeting the protein would enable localized lesion regulation without disrupting the systemic immune system. This could lower potential tumorigenic risks and other adverse reactions, the researchers say.

Taken together, the results “suggest that CHI3L2 expression is induced in patients with psoriasis and is associated with disease progression and treatment,” write Li and co-authors.

They conclude that “circulating CHI3L2 could be used as a biomarker and may also play a pathogenic role in disease.”

The post Psoriasis Inflammation: CHI3L2 Emerges as a Potential Therapeutic Target appeared first on Inside Precision Medicine.

Called BIOSENTER, the robotic enteroscope was developed to address the challenges of reaching parts of the digestive tract that are difficult to examine using existing medical procedures. The small intestine is more than 20 feet long and much harder to access than other parts of the digestive system, such as the stomach and colon. 

Currently, the only established option to diagnose complications in the small intestine, including bleeding, lesions, and blockages, is a procedure known as double-balloon enteroscopy, where two inflatable balloons are used to move the endoscope through the intestine. However, the procedure can be slow and laborious, prompting researchers to explore alternatives that offer greater control and faster movement.

“The fundamental challenge that we’re trying to overcome is how to evaluate that 20-to-25-foot segment of the small intestine in a way that can be more automated,” said Giovanni Traverso, MD, PhD, professor of mechanical engineering at MIT, gastroenterologist at Brigham and Women’s Hospital, and associate member of the Broad Institute of MIT and Harvard. 

BIOSENTER takes inspiration from snakes, which propel themselves forward by coordinating muscle contractions on both sides of their bodies. The robot’s tube-like body contains four inflatable chambers that can expand or contract in different combinations, allowing the robot to move forward and bend in different directions. 

Its head and tail feature additional inflatable segments that take turns anchoring and releasing their grip on the intestinal wall to propel the device forward. These segments are wrapped in sleeves inspired by kirigami, the Japanese art of cutting paper to create three-dimensional structures. When the sleeves expand, tiny needle-like features emerge from their surface, helping the robot grip the intestine’s slippery mucosal lining.

“By tuning the amount of air that goes into these chambers, you can tune the direction that the robot is moving in,” said Traverso. “Using kirigami sleeves to enhance surface friction, the robot can generate localized locomotion without relying on excessive stretching of the delicate small intestinal tissue.” 

A hollow central channel allows the robot to carry endoscopic tools, including a camera for imaging, a fluid sprayer for drug delivery, and clips for collecting tissue samples or removing small polyps. The robot is designed to enter the body through either the mouth or the rectum, and remains connected to an external control box through a cable. 

In live pigs, the system navigated approximately two meters of collapsed, winding small intestine in 11 minutes, demonstrating its ability to capture real-time images, collect small tissue biopsies and deliver fluid to specific locations. No visible tissue damage or overdistention were reported during the animal tests.

The team is now working to improve the robot’s navigation systems and investigate additional applications within the small intestine. “We hope we can continue to move it forward to eventually develop systems that can help achieve more automated evaluation of the small intestine,” Traverso said.

The post Snake-Like Soft Robot Could Diagnose and Treat Small Intestine Disorders appeared first on Inside Precision Medicine.

Looking at both complete responders to CD19-directed chimeric antigen receptor (CAR) T-cell therapies and those with progressive disease the researchers were able to show how individual CAR T-cell clones expanded and persisted, whether malignant B cells were being destroyed, and whether other tissues were being injured just by looking at blood samples.

Blood tests analyzing cfDNA from tumors already help identify mutations and select targeted cancer treatments. They can also provide information about treatment response, residual disease, and relapse risk, although using these findings to guide treatment remains investigational.

Daniela Cesana, PhD, a group leader at the San Raffaele Institute, and colleagues previously developed a technique called the LiBIS-seq method, originally developed to monitor gene therapy by retrieving vector integration sites from cfDNA and detecting engineered clones, including those in peripheral tissues, more comprehensively than conventional blood-cell analysis.

“We demonstrated that this is a very powerful approach because if adverse events in gene therapy occur, for example, bad growth in solid tissue like in the case of lymphoma… conventional integration studies failed to detect the presence of these tumors,” Cesana told Inside Precision Medicine.

“The cfDNA strategy was much more powerful in detecting this because these tumors are releasing these fragments and these fragments can be captured by our approach.”

For this study, presented at the European Society for Cell and Gene Therapy conference in Hamburg by Cesana, the researchers followed 16 people with relapsed or refractory B-cell malignancies receiving commercial CD19-directed CAR T products. Eight had a complete response at day 90 and eight had progressive disease.

The researchers collected blood samples for up to a year and using this information and the previously developed technique they identified vector integration sites, the genomic locations where the CAR construct entered each engineered T cell. Each site effectively labels a clone, so this allowed them to reconstruct the diversity, expansion, and persistence of the CAR T cells used to treat the patients. They also used DNA-methylation patterns to estimate which cells or tissues had released the cfDNA, including B cells, neurons, and liver cells.

The results showed complete responders had a much broader and more persistent CAR T-cell repertoire: 98,482 unique integration sites versus 2,906 among non-responders. Overall, responders had a high total cfDNA concentration before treatment followed by a decline in levels. In contrast, concentrations of cfDNA remained stable or increased in non-responders.

B-cell-derived cfDNA was high in patients with active disease before infusion and during the first two weeks afterwards, potentially reflecting baseline tumor burden followed by CAR T-cell mediated killing. A stronger B-cell cfDNA signal was associated with less CAR T-cell expansion. This suggests that high disease burden, cellular turnover, or inflammation may impair CAR T-cell performance, although the study cannot establish causality.

Cesana and team were also able to assess if neuronal or liver-cell injury had occurred as a result of CAR T-cell side effects such as cytokine-release syndrome, neurotoxicity, or other inflammatory complications by looking at methylation signatures of the cfDNA fragments.

“There is a progressive increase in the amount of fragments that are produced by the targeted tissue, such as the liver and the central nervous system, and this increase occurs even before the clinical symptoms begin,” explains Cesana.

This study was a small exploratory study, but it demonstrates the potential of cfDNA as a multipurpose biomarker for patients undergoing CAR T-cell therapy, with additional potential to identify possible side effects at an early stage.

“This approach could help clinicians in the future in selecting the best personalized approach to treat their patients,” says Cesana. “It could help with the selection of the therapeutic strategy, the conditioning approach, the type of therapy, and other factors,” she adds, although concedes that more data and research validation studies are needed before this technique can be used more widely in the clinic.

The post Cell-Free DNA Provides Insight on CAR T-Cell Efficacy, Toxicity appeared first on Inside Precision Medicine.

Their paper appears in BMJ Journals’ Gut, and the senior author is Ajit Harishkumar Goenka, MD, Department of Radiology, Mayo Clinic, Rochester.

“What we did differently was design it around the problems that usually make an early-detection model difficult to translate into actual practice,”  Goenka told Inside Precision Medicine. “We made the entire process automated and trained and tested it in a much more difficult setting where normal scans substantially outnumbered cancer cases, which is closer to what early detection looks like in the real world.” 

REDMOD uses radiomics to analyze extremely fine pancreatic tissue patterns, which are not readily visible by conventional computed tomography (CT) scans. The AI also automatically identifies and outlines the pancreas, separating it from nearby organs and tissues. Currently, specialists must manually trace the organ’s boundaries, which is not only time consuming but introduces variability by practitioner.

Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is often discovered only after the disease has advanced beyond the reach of treatment, and progresses rapidly. 

Goenka’s team started with nearly 1,000 quantitative measurements of pancreatic tissue: “We found that the most informative signals were not obvious changes in shape or size, but very subtle patterns of tissue texture at multiple spatial scales. Finally, instead of relying on one machine-learning algorithm, REDMOD combines three different algorithms and averages their predictions.”

To evaluate the system, the researchers examined abdominal CT scans from 219 patients treated at multiple hospitals. Experienced radiologists had found no evidence of pancreatic cancer at the time of these patients’ scans. However, every patient in this group was subsequently diagnosed with the disease.

The scans were taken at different intervals before diagnosis. For 87 patients (40%), the images were obtained three to 12 months earlier. Another 76 patients (35%) had been scanned 12 to 24 months before diagnosis, while 56 (25%) had undergone imaging more than 24 months earlier (up to around three years). In nearly two thirds (64%) of the patients, the cancer developed in the head of the pancreas.

The researchers also assessed how well the system could recognize scans from people without pancreatic cancer. In an independent group of 539 patients from several hospitals, REDMOD correctly classified just over 81% of scans as cancer free. It performed even better on the publicly available U.S. National Institutes of Health NIH-PCT dataset (80 patients), correctly identifying 87.5% as free of pancreatic cancer.

The team emphasized that more research is necessary before the system can be introduced into routine medical care. In particular, they said, the system must be tested in patients at high risk, including those experiencing unexplained weight loss or recently diagnosed diabetes.

AI is already part of radiology practice in a number of areas, Goenka pointed out. For example, systems to help diagnose acute stroke, intracranial hemorrhage or pulmonary embolism, and mammography.

“REDMOD presents a harder problem,” he said. “Most existing tools alert the physician to an abnormality that can then be seen and verified. REDMOD is intentionally looking for disease at a stage when the pancreas may still look normal. If the computer says there is an abnormal signal but the radiologist cannot see a tumor, what should happen next?”

Goenka added, “That is the key translational question. We need to define who should receive the analysis, how a positive result should be presented, when it should trigger repeat imaging or endoscopic ultrasound, how false positives should be handled, and how to prevent physicians from either blindly accepting or reflexively dismissing an AI result.” 

His team will follow up with prospective studies, broader multi-center validation across different patient populations and imaging systems, and the regulatory and other requirements to introduce the system to the clinic.

“We first need to know whether the performance we observed retrospectively holds when we identify high-risk individuals and study them prospectively,” he said. “We are also working on the question raised above: where exactly is the earliest AI signal within the pancreas, and how should a physician respond when the AI is positive but conventional imaging remains normal? Ultimately, those questions are as important as the accuracy of the algorithm itself.”

The post Pancreatic Cancer Could Be Detected Much Earlier with Mayo Clinic AI appeared first on Inside Precision Medicine.

For 17 years, that individual has struggled with radiation-induced xerostomia, a debilitating side effect of head and neck cancer treatment that impairs saliva production. Everyday activities such as eating, swallowing, and speaking had become difficult and, at times, dangerous. A few weeks after receiving an experimental therapy called RXRG001 from RiboX Therapeutics, his ability to produce saliva came back. Later, while eating a cookie, the same person realized he could form a food bolus and swallow without drinking water for the first time in years.

This patient represents one of six patients treated with RXRG001, a circular RNA (circRNA) drug encoding the water channel aquaporin-1 (AQP1) designed to restore salivary function in patients with radiation-induced xerostomia. Unlike conventional messenger RNA (mRNA), which forms a covalently closed loop, protecting it from degradation to support, theoretically, sustained protein production.

Last week, RiboX Therapeutics reported initial findings from this small Phase I trial testing RXRG001 in radiation-induced xerostomia patients in a The New England Journal of Medicine study. The findings from the “Study of Circular RNA Treatment in Patients with Radiation-Induced Xerostomia-1 (SPRINX-1)” trial demonstrate that RXRG001 increased saliva production in patients with chronic dry mouth, providing early evidence that circRNA can produce measurable therapeutic benefits in humans. This is the first published clinical trial of a circRNA drug as a therapeutic agent, a milestone for RNA medicine.

For patients, the significance extends beyond the clinical measurements. “When we look at the paper and those numbers, it’s kind of cold because we don’t know how those numbers change patients’ lives,” said RiboX Therapeutics’ CEO, Weiyi Zhang, PhD, in an interview with Inside Precision Medicine. It’s in the anecdotes of tiny subconscious actions and moments people take for granted that really captures the significance of RXRG001.

The findings from the trial offer an early clinical proof of concept for circRNA therapeutics, although questions remain about the durability, consistency, and safety of the response. Enrollment in the ongoing study continues, with investigators evaluating dose–response relationships, duration of effect, and longer-term safety at higher dose levels.

Simplifying for proof-of-concept

The concept of using AQP1 to treat radiation-induced xerostomia is not entirely new. Clinical studies have demonstrated that viral vectors carrying the AQP1 gene can increase salivary epithelial cell water transport and may restore salivary function. RXRG001, provides a non-genome integrative therapeutic option by enclosing an AQP1 circRNA in a lipid nanoparticle (LNP).

In a procedure that takes less than 10 minutes, RXRG001 is delivered directly into the patient’s parotid gland, which is the major salivary gland responsible for producing thin and watery saliva. The localized administration simplifies the procedure and offers a relatively direct way to evaluate therapeutic activity, an important consideration for the company’s first clinical program, which focuses on proof-of-concept with deliberate and clear biological readouts. “For our first program, we wanted to read out exact pharmacodynamic markers,” Zhang said. “That means we needed to know that the drug was working.”

The ongoing Phase I trial enrolled six patients with chronic xerostomia following radiation treatment for head and neck cancer. All had experienced the condition for at least two years. Three patients received 4 μg of RXRG001, while three received 10 μg. Each underwent a single infusion into one parotid gland.

The treatment was generally well tolerated in this small cohort. No dose-limiting toxic effects associated with the infusion procedure were observed during at least 120 days of follow-up. Treatment-related adverse events were transient and limited to grade 1 or 2 severity, including low-grade fever, fatigue, and chills. However, with only six patients, no control group, and limited follow-up, larger studies will be necessary to establish the magnitude, consistency, and durability of benefit, as well as longer-term safety.

Exceeding durability expectations

Led by Henry T. Hoffman, MD, an otolaryngologist specializing in head and neck cancer at the University of Iowa Health Care Medical Center, investigators measured unstimulated and stimulated saliva production alongside patient-reported assessments of dry mouth symptoms and their impact on daily life.

Hoffman and colleagues found that salivary flow increased substantially from baseline, with improvements evident as early as seven days after treatment and maintained through day 90. Among patients receiving the lower dose, the unstimulated whole-saliva flow rate increased from baseline to day 90 by 47% in Patient 1, 300% in Patient 2, and 450% in Patient 3. The stimulated whole-saliva flow rate increased by 55%, 1450%, and 131%, respectively, during the same time period. Similar increases were observed in the higher-dose cohort.

Patient-reported outcomes generally supported the physiological measurements, showing rapid reductions in dry mouth symptoms during the first month and improvements that persisted during follow-up. 

One of the more intriguing findings was the duration of the response. The company expected patients to need repeated interventions to maintain therapeutic benefit. “We needed to figure out the interval between doses,” Zhang said. “Initially, I thought it would probably be a one-month interval. Then we kept waiting for the patients to relapse.” Instead, improvements persisted for months following a single administration. “Even the six-month duration was already a big surprise to us,” Zhang said.

Several factors could contribute to the prolonged response, such as the inherent stability of circRNAs. In preclinical rodent experiments, the circRNA served as “a local depot for protein expression,” resulting in protein expression lasting over a month, Zhang said. 

But RNA stability alone may not explain the duration of the clinical response. AQP1 expression may trigger biological processes that improve gland function after protein production. “The protein expression may also trigger downstream signaling that helps restore gland function,” Zhang said. According to Zhang, RiboX will investigate this hypothesis as clinical data becomes available.

Making next-generation RNA drugs

Beyond the clinical findings, the study provides an early demonstration of the manufacturing and delivery capabilities needed to translate circRNA into a therapeutic platform. CircRNA presents different engineering challenges from conventional mRNA. Whereas linear mRNA typically relies on a 5′ cap and a 3′ poly(A) tail, synthetic circRNA must incorporate alternative mechanisms to initiate translation.

RiboX uses internal ribosome entry sites (IRES) to drive protein production. “We have much more room for engineering,” Zhang said. “We use internal ribosome entry sites, or IRES elements, to drive protein expression.” The company has explored different regulatory elements and circularization strategies to optimize protein production, stability, and manufacturing efficiency.

To manufacture its circRNA, RiboX begins with a DNA plasmid template and generates a linear RNA precursor through in vitro transcription. A self-splicing catalytic intron then facilitates circularization. The company has evaluated hundreds of catalytic intron designs to identify suitable configurations for individual therapeutic programs. RiboX conducts process and analytical development internally before transferring its manufacturing process to a contract development and manufacturing organization for clinical production.

The company also sees opportunities to expand the range of proteins that RNA therapeutics can encode. According to Zhang, RiboX has shown that circRNA can encode the longest human gene, dystrophin, which is essential for Duchenne muscular dystrophy. “We don’t see a limitation on size,” Zhang said, although practical constraints associated with RNA production, delivery, and translation remain important considerations.

A materializing big pharma magnet

RiboX is hardly alone in betting that circular RNA could overcome some limitations of conventional mRNA therapeutics. A growing group of biotechnology companies is developing competing circRNA platforms, with much of the industry’s attention shifting toward in vivo cell engineering. That interest has translated into substantial dealmaking.

In February 2026, Eli Lilly announced an agreement to acquire Orna Therapeutics for up to $2.4 billion, expanding its capabilities in genetic medicine and in vivo CAR T therapy. Orna’s lead candidate, ORN-252, is a CD19-directed in vivo CAR T therapy designed to treat B-cell-driven autoimmune diseases.

Another prominent competitor, Orbital Therapeutics, was acquired by Bristol Myers Squibb for $1.5 billion in a transaction completed in December 2025. Its lead candidate, OTX-201, uses targeted lipid nanoparticles to deliver circRNA encoding a CD19-directed chimeric antigen receptor, with the goal of engineering T cells directly inside the body.

Meanwhile, Sail Biomedicines, formed through the combination of Flagship Pioneering-backed Laronde and Senda Biosciences, integrates its Endless RNA technology with targeted nanoparticles designed to deliver circRNA to selected immune cell populations. In July 2026, Johnson & Johnson entered a collaboration with Sail involving $785 million in initial payments and commitments, including a $465 million equity investment, and secured an exclusive option to acquire the company for an additional $2.58 billion.

Other companies are pursuing distinct approaches. Norway-based Circio is developing its circVec platform, which uses genetic vectors to generate circular RNA inside target cells rather than administering premanufactured circRNA directly. The company is also exploring in vivo CAR T applications. Shanghai-based CirCode Biomed is advancing HM2002, a circRNA therapeutic encoding vascular endothelial growth factor A (VEGF-A) for ischemic heart disease. Like RiboX, CirCode has moved into human clinical testing, highlighting the expanding clinical footprint of the modality.

RiboX’s distinction is its publication of early clinical results demonstrating measurable physiological improvement following administration of a circRNA drug. This does not establish that RXRG001 was the first circRNA therapeutic ever administered to a human.

The circular structure and how well RNA is manufactured, delivered to tissues, translated into protein, and sustained at therapeutically meaningful levels may determine the competitive landscape.

Beyond the salivary gland

For RiboX, the lessons learned from RXRG001 provide a foundation for broader ambitions. “Understanding the durability of circRNA, its encapsulation, and how to optimize the entire system will help us in the next step,” Zhang said.

The broader objective is to expand RNA delivery beyond the liver, which has historically been the most accessible organ for systemically administered lipid nanoparticles. Eventually, the company believes the approach could have applications in oncology as well.

One area of interest is in vivo CAR T-cell therapy, which could potentially reduce the complexity, cost, and manufacturing delays associated with conventional autologous CAR T-cell therapies. That next step involves attaching targeting antibodies to LNPs, or targeted LNPs (tLNPs), to direct circRNA delivery toward specific immune cell populations. The company is initially interested in established B-cell targets, including CD19, CD20, and BCMA, with an emphasis on chronic diseases rather than cancer.

Whether transient circRNA expression can generate potent and durable immune responses in patients for different indications has yet to be demonstrated. For now, the company’s published clinical results offer a narrower but meaningful proof of concept: circRNA can be delivered to human tissue and produce a measurable therapeutic effect.

The post Circular RNA Shows Clinical Promise in First Published Results from RiboX appeared first on Inside Precision Medicine.

The findings, outlined in three papers in Nature, could speed the development of targeted treatments and precision medicines for a range conditions, from multiple sclerosis to Alzheimer’s disease to cancer.

The research traces how DNA variation affects gene expression at different levels and covers the function of more than five million immune cells in nearly 2000 Australians, making use of the largest dataset of its kind to date.

Tracing tens of millions of genetic variants revealed how immune cells were likely involved in risk regions for 16 diseases and highlighted nearly 1500 genes potentially implicated in a variety of diseases.

“With our findings, we’ve gone from understanding very few to thousands of the potential causal mechanisms connecting genetic variation to disease risk, which is huge,” said Joseph Powell, PhD, from the Garvan Institute of Medical Research in Sydney, Australia, who co-authored all the research papers.

“This is a fundamental shift in what’s possible. When you know which genetic variant is driving a disease—and in which cell, through which mechanism—you can start to identify patients who are likely to respond to a particular treatment, and develop drugs toward targets we didn’t know existed.”

All the findings come from phase one of the TenK10K project, which used the latest RNA single-cell technology to sequence the genomes of 1925 Australians.

Using this information, researchers were able  to measure the genetic activity of 5.4 million immune cells across 28 immune cell types, with each of the studies investigating a different level of gene regulation.

In the first study, a team led by Anna Cuomo, PhD, also from Garvan, examined the impact of common and rare genetic variants across different cell types. They identified common effects for 83% of the 21,404 genes tested and rare effects for 47% of those genes.

Overall, there were 164 independent genetic variants that regulated the abundance of cell states. The study also showed that 893 genes linked with diseases or blood traits that had not previously been associated with genetic variation.

The second study investigated the impact of tandem repeat variation—repetitive DNA sequences that are important for genetic regulation and take up a larger proportion of the genome than protein-coding genes. Specifically, Hope Tanudisastro, PhD, also from Garvan, and co-workers looked at how these tandem repeat differences affected different immune cells.

The team identified more than 69,000 tandem repeat variants, 30.7% of which were specific to one of 28 immune cell types and revealed dynamic regulatory effects.

More than 200 genes were identified that likely mediated genetic associations with immune and hematological traits and could be potential new targets for treatment.

The final study examined how genetic variants and disease risk were shaped by chromatin accessibility—the spatial architecture of DNA as a way to control the expression of genes.

Angli Xue, PhD, from Garvan, and co-workers identified 243,225 variants linked with chromatin accessibility. Overall, 28,834 of the DNA regions were linked with genes they could help regulate.

Chromatin accessibility likely explained up to 22.6% more genetic regions linked with diseases than simple gene activity in isolation.

Powell explained how most of the biological mechanisms uncovered by the research teams were invisible in prior studies.

“This pinpoints the immune cell type involved, which could help target future treatments,” he explained.

“For example, we found a genetic variant that increases the expression of a gene called OSM in natural killer immune cells and increases the risk of developing irritable bowel disease.

“This uncovered a specific immune pathway that could potentially be targeted with future treatments.”

The post Genetic Differences Impact Immune Cells to Affect Disease Risk appeared first on Inside Precision Medicine.

The findings, in Nature Communications, reveal how using a protein carrier can extend the time that these medications are biologically active and allow them to delivered through non-invasive means such as the nose.

Researchers discovered the benefits by fusing the hormone erythropoietin (EPO)—which is used to boost the production of red blood cells in patients with anemia—to an engineered form of human albumin in mice.

Through this, they created a long-acting molecule with extended biological activity that remained longer in the circulation.

“This study shows how an understanding of the fundamental biology that regulates albumin homeostasis can be used to design engineered albumin-fused biologics with tailored transport properties,” explained senior researcher Jan Terje Andersen, PhD, from the University of Oslo.

He added: “Instead of only focusing on the therapeutic protein itself, we have engineered its carrier. By doing so, we can control how long the fusion protein stays in the circulation and, at the same time, improve its ability to cross selective biological barriers.”

Albumin usually exists in the circulation for around three weeks because it binds to the neonatal Fc receptor FcRn, which is a key regulator of its half-life in plasma.

In an attempt to harness these qualities of FcRn, the team led by Aina Karen Anthi, PhD, also from the University of Oslo, genetically fused EPO to an albumin variant QMP, which was engineered to improve pH-dependent binding to human FcRn.

They found that when this was delivered intravenously to mice engineered to express human FcRn, it lasted several times longer in the circulation without affecting the therapeutic value of EPO.

The plasma half-life of the engineered combination was 5.7 days versus just 1.1 days when EPO was fused to normal human albumin.

While EPO was combined with the engineered albumin it was detected in the animals’ circulation for up to 27 days compared with just 10 days when using regular albumin.

The combination using the engineered albumin bound to the EPO receptor with a similar efficacy to commercially available long-acting EPO product and was effective in stimulating erythrocyte production.

In addition, erythrocyte levels remained higher for far longer with the former than the latter.

The researchers then asked whether engineered albumin could act as a molecular carrier to transport EPO across mucosal barriers.

They found that five times more of the engineered albumin combination reached blood when it was delivered intranasally in mice than when regular albumin was used.

The protein also retained its function, and resulted in a stronger and more prolonged erythrocyte increase than when the commercially available EPO product was used.

“Our results show that we can use QMP and its receptor, FcRn, as a transport system,” said Andersen.

“This could potentially contribute to protein-based medicines that can be given less frequently—and perhaps, for some applications, without needles.”

The post Engineered Albumin Improves Longevity and Delivery of Protein-Based Therapeutics appeared first on Inside Precision Medicine.

The computational approach, described in Cell Reports Medicine, uses patient genomic data to create tumor “digital twins” that simulate cancer cell behavior and predict the effects of different treatments. The models correctly predicted treatment responses in 74% of cases and identified potential additional therapies for 12 of 13 patients whose cancers had not responded fully to treatment.

TNBC accounts for approximately 15% of breast cancers and is particularly challenging to treat because it lacks the estrogen, progesterone, and HER2 receptors targeted by many established breast cancer drugs. Although chemotherapy, immunotherapy, and PARP inhibitors have expanded treatment options, responses vary considerably among patients.

To address this variability, researchers developed a computational model using symbolic artificial intelligence, which relies on logical rules and known biological interactions rather than statistical pattern recognition alone. Unlike conventional machine-learning approaches that may not explain how predictions are generated, the model allows researchers to examine the molecular mechanisms underlying its recommendations.

The team personalized the models using genomic data from 31 patient samples collected during the PARTNER clinical trial at the University of Cambridge and Addenbrooke’s Hospital. The trial evaluated combination chemotherapy with or without the PARP inhibitor olaparib. The researchers simulated both treatment regimens, along with untreated controls, and compared the predicted outcomes with actual patient responses.

For 10 of the 13 patients who had not responded fully, the models predicted that adding targeted therapy could potentially produce a pathological complete response, meaning no invasive cancer would remain detectable in the breast or lymph nodes after treatment. These benefits were computational predictions, not observed clinical outcomes.

ATM inhibition emerged as the most broadly promising strategy, particularly in tumors with genetic alterations associated with increased DNA replication stress. Inhibiting ATM, a protein involved in repairing damaged DNA, could prevent cancer cells from recovering from chemotherapy-induced damage.

Other predicted vulnerabilities included Chk1 and ATR, particularly among patients receiving olaparib alongside chemotherapy. Wee1 inhibition also showed potential, while mTOR inhibition appeared beneficial in a smaller subset.

Although these molecular targets have previously been investigated in TNBC, clinical results have been mixed. The researchers suggest that identifying patients with specific molecular vulnerabilities could improve treatment selection and help explain why targeted therapies benefit some patients but not others.

The team also identified mutational and gene-expression biomarkers associated with treatment response. Testing these signatures against an independent breast cancer cohort from The Cancer Genome Atlas showed that they could distinguish patients with significantly different overall survival outcomes.

Future research will focus on validating these therapeutic strategies and developing practical biomarker tests that could guide treatment selection without requiring a complete digital twin for every patient.

The post Virtual Tumor Models Reveal Promising Treatment Strategies for Triple-Negative Breast Cancer appeared first on Inside Precision Medicine.

The research, presented at the European Society for Cell and Gene Therapy congress in Hamburg and carried out at University Hospital Zürich, shows LILRB2 expression impaired CD33-targeted CAR T-cell killing, expansion and cytokine production, and was associated with signs of T-cell exhaustion.

The researchers showed that blocking LILRB2, which is involved in suppressing immune responses, partially restored CAR T cells’ ability to attack leukemia cells. They suggest this approach could help make CAR T-cell therapies more effective against the aggressive blood cancer.

“AML is a common and aggressive hematologic malignancy with poor outcomes,” write presenting researcher Silvan Brunn, PhD, University Hospital Zürich, and colleagues. Around 70% of patients die within five years.

“Although CAR T-cell therapies have shown major clinical benefit in other hematologic cancers, their efficacy in AML has been limited by the lack of targets that can be safely engaged without posing a risk of myeloablation, as well as by a strong immunosuppressive tumor microenvironment.”

While LILRB2 was previously observed in AML and other cancers, the link with CAR T cell function was unclear. In this study, the researchers looked into this association further.

The team observed that LILRB2 was overexpressed on a significant number of AML cells and mostly absent from healthy hemopoietic stem and progenitor cells. They also saw that presence of this protein seemed to reduce the anti-cancer functionality of CD33-targeted CAR T cells.

Brunn and co-researchers manipulated LILRB2 expression in leukemia cells and tested whether blocking it improved the cancer-fighting efficacy of CD33-targeted CAR T cells.

“Transcriptomic analyses revealed downregulation of immune response pathways in both effector and target cells and induction of T-cell senescence programs, providing a mechanistic basis for the decreased CAR T-cell functionality, which was partially restored by LILRB2 inhibition using blocking antibodies,” they write.

The team also developed CAR T cells that directly recognize LILRB2. These CAR T cells eradicated tumors in one leukemia cell-line mouse model and also showed activity against patient-derived leukemia. There was no evidence of toxicity or destruction of blood-forming marrow in the humanized-mouse experiments.

While the results are early, they identify LILRB2 as an important regulator of CAR T-cell dysfunction in AML. They also support targeting this cell surface protein by developing new drugs to target it, says Brunn, or by using CAR-based approaches to enhance CAR T-cell therapy for treating AML.

The post Target for Improving CAR T-Cell Therapy Efficacy in AML Uncovered appeared first on Inside Precision Medicine.

As reported in Cell Metabolism, the researchers also found the same miRNAs, which function to regulate genes, in the breastmilk of female mice showing depressive symptoms and investigated their impact on exposed offspring.

In the mouse model, the three miRNAs reduced production of mGluR8, a protein on nerve cells that acts like a brake on the signals they send by reducing the release of glutamate. Glutamate is a chemical messenger that activates other nerve cells and helps prevent excessive stimulation. With this brake weakened, developing neurons in the hippocampus part of the brain of the young mice received more frequent stimulating signals, matured abnormally and integrated less successfully into brain circuits.

“Postnatal depression, or postpartum depression, affects approximately 10%–20% of women worldwide and poses significant health risks to both mothers and offspring,” write the authors.

“Affected mothers may exhibit depressed mood, apathy, disrupted appetite and sleep, cognitive impairments, and suicidal ideation, while their children face increased risks of delayed cognitive and language development, behavioral challenges, poorer academic achievement, and depression extending into adolescence.”

Although research on postnatal depression has revealed more information about the condition, the way that maternal postnatal symptoms impact their offspring is not well understood. “Postnatal depression and breastfeeding exhibit a bidirectional relationship: postnatal depression reduces exclusive breastfeeding and promotes early cessation, whereas breastfeeding lowers postnatal depression incidence,” explain the team.

Although breastfeeding can be beneficial to the mental health of the mother, it is not clear what the impact of postnatal depression is on breast milk composition. “Postnatal depression can dysregulate physiological and metabolic pathways, potentially altering breastmilk composition. Such modifications may adversely affect infant cognitive, behavioral, and psychological development, potentially offsetting the established benefits of breastfeeding.”

In this study, the authors compared breastmilk microRNAs, from 40 mothers with postnatal depression and 51 without. They found three, miR-15a-5p, miR-15b-5p and miR-205-5p, were elevated in women with postnatal depression and also in model mice with the condition.

The team swapped newborn pups between stressed and unstressed mothers to distinguish effects after birth from those during pregnancy. To isolate milk’s contribution from maternal care, they also gave pups raised by healthy mothers purified human-milk extracellular vesicles, tiny membrane-wrapped particles carrying microRNAs.

The researchers looked at the impact of exposure to the specific miRNAs on pup neuronal development. They found the three milk-borne microRNAs reached the brain and suppressed mGluR8. This disrupted the maturation and integration of newly formed hippocampal neurons. Exposed mice developed learning and memory problems that persisted into adulthood and offspring raised by stressed mothers also showed greater depression-like responses after stress.

Notably, reducing milk-vesicle release, neutralizing the three microRNAs linked to postnatal depression, or restoring mGluR8 prevented or substantially reduced several neuronal abnormalities.

The study results do not show that breastfeeding by mothers with depression harms infants or justifies stopping breastfeeding. However, the study suggests that breast milk’s molecular signals could contribute to developmental effects associated with maternal depression and should be investigated further.

“Our findings define a mechanism underlying postnatal depression-related offspring neurodevelopmental impairments and suggest a therapeutic target for interrupting the intergenerational transmission of maternal mental disorders,” conclude the authors.

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