This prognostic study of 159 triple negative breast cancer (TNBC) patients found the tissue-free assay was “highly prognostic” for recurrence, according to the authors. The test detected minimal residual disease (MRD) as soon as the multivariate tumor biopsy-informed assay, and with a longer lead time than digital polymerase chain reaction (dPCR).

The authors wrote: “These findings support tissue-free ctDNA detection in the molecular residual disease setting, allowing testing when archival tissue is unavailable.”

The study appeared on August 13 in JAMA Network. The lead author is Niamh Cunningham, MBBS, of the Ralph Lauren Centre for Breast Cancer Research at the Royal Marsden Hospital in London, and the senior author is Nicholas C. Turner, MD, PhD, also at the Royal Marsden.

ctDNA has very quickly become one of the most studied areas of oncology. Since curing cancer is thought to depend on eliminating MRD, doctors are keen to do this. Tumor biopsies provide a sort of blueprint on how to treat cancers with the drugs on hand. But scientists want to know more about why some tumors spread despite treatment and how to stop them.

TNBC has a high risk of recurrence and mortality. It is hard to treat, and patients are at particular risk of receiving potentially excessive doses of toxic therapy. But it has been difficult to detect MRD for TNBC. Now, recent studies suggest ctDNA may offer a new approach. This technique has shown great promise as a sensitive and highly specific means of detecting molecular traces of malignancies. 

This U.K. study was a prognostic, exploratory analysis of TNBC patients at moderate to high risk of recurrence who were participating in c-TRAK TN, a multicenter Phase II clinical study. Plasma samples were collected from participants every three months for up to two years after the completion of adjuvant therapy and analyzed prospectively with dPCR. 

Final analysis included 1,026 plasma samples from 159 patients. The tissue-free assay detected ctDNA in 54 patients (34.0%)—detection was strongly associated with risk of recurrence. Among patients with ctDNA detected by both the tissue-free assay and dPCR (42 patients, or 26%), tissue-free detection occurred earlier in 14 patients (33.3%). dPCR detection did not occur before tissue-free detection in any patient.

These findings build on a steadily growing body of research about ctDNA for MRD detection.

Also, recently, another study analyzed the potential for ctDNA to predict pathologic complete response (pCR) in TNBC.

PREDICT-DNA was a prospective study that enrolled patients with stage II through III TNBC and tested ctNDA as a biomarker of treatment response. The team used a tumor-informed, ultrasensitive assay that could detect variants at ≤100 parts per million. Almost all of the 227 patients enrolled were evaluated for pCR assessment.

“Although this study did not meet its primary endpoint, of demonstrating that post-neoadjuvant ctDNA negativity predictive pCR with a negative predictive value of > 90%, its secondary findings are arguably more clinically meaningful,” wrote Bryan P. Schneider, MD, and Daniel G. Stover, MD, in an accompanying editorial.

The post ctDNA From Blood Equals or Bests Tissue-Based Tests in Triple Negative Breast Cancer appeared first on Inside Precision Medicine.

Writing in Science Translational Medicine, the researchers report that while the treatment showed some signs of efficacy and side effects were manageable, it didn’t fully meet its primary or secondary endpoints.

“The BE-CAR33 T cells showed signs of activity and were detectable in the blood and bone marrow. Responses were encouraging, but deeper clearance of AML would have been better,” lead author Waseem Qasim, a professor at UCL Great Ormond Street Institute of Child Health in London, told Inside Precision Medicine.

First-generation CAR T cell therapies have been approved to treat certain blood cancers for the last nine years. These therapies use a patient’s own T cells, engineered to target cancer, which limits their use in sick or heavily pretreated patients.

BE-CAR33 is one of several next-generation CAR T cell therapies made with donor T cells. Donor T cells can be rejected in the same way as a transplanted organ, but BE-CAR33 T cells were made safer using base editing to disable three genes to prevent organ rejection, immune attack on the cells themselves, and evasion by the leukemia.

This builds on the team’s earlier work to treat a different leukemia type, extending “off-the-shelf” universal donor-cell approaches to AML, which has historically resisted CAR T cell therapy success due to having shared antigens with healthy bone marrow.

“Previously, we applied similar base editing techniques to treat T cell leukemia. This new study aimed to extend the approach of using ready-made, off-the-shelf CAR T cell therapy for AML,” said Qasim.

“That’s a much more difficult target because the surface flags targeted by the CAR T cells are less consistent and can change. This is the first time in the U.K. a study has targeted a flag called CD33.”

Overall, three children and one adult with relapsed AML received the BE-CAR33 T cell therapy before a planned stem cell transplant, the standard therapy for AML.

While no acute infusion-related toxicities occurred, the therapy caused expected but significant side effects, including cytokine release syndrome, low blood cell counts, and, in one patient, a grade 3 neurotoxicity and an over-activated inflammatory state. This meant the primary endpoint of establishing the safety of this therapy was not completely met.

The secondary study objectives were to determine anti-cancer efficacy and to assess disease-free and overall survival, and how successfully the new, healthy blood-forming cells from a donor take over and start making blood cells again after a transplant.

The secondary outcomes were mixed. Half the patients had a low enough disease burden 21 days after the treatment to proceed to a bone marrow transplant, but long-term outcomes were poor overall. The engineered cells were detectable in blood and marrow after infusion and were then successfully eliminated by conditioning chemotherapy ahead of transplant, with no lasting off-target safety issues.

Although the results of this study could have been better, the researchers say they provide important information to guide future studies and show this kind of treatment approach is feasible.

“I think for AML, we will need to target multiple surface markers—alongside CD33. Suitable flags might include CD7 or CD38 and other proteins,” said Qasim.

“Next stage studies will combine BECAR33 with other cells for a combination-approach tailored to an individual patient’s disease.”

The post “Off-the-Shelf” CAR T-Cell Therapy Shows Mixed Early Results appeared first on Inside Precision Medicine.

Researchers have identified three cell-surface proteins with potential as therapeutic targets in cervical cancer, while demonstrating a strategy that could help match patients with antibody-based treatments based on the molecular characteristics of their tumors.

The study, published in Computational Biomedicine, combined gene expression data from hundreds of cervical tumors with laboratory testing of antibody-drug conjugates (ADCs) directed against three potential targets: mesothelin (MSLN), TROP-2, and LIV-1.

For principal investigator Stefan Barth, PhD, of the University of Cape Town, the study builds on a broader question his group has been exploring: What makes a cancer protein a genuinely useful target?

Tumor-associated antigens are proteins found on normal cells but expressed at higher levels on cancer cells. Barth and his colleagues previously developed a transcriptomic approach for comparing cell-surface targets in tumors with their expression in healthy tissues, initially demonstrating the strategy in breast cancer. The broader research program has examined the approach across 26 cancer types.

“We were looking for what we were calling ideal targets,” Barth told Inside Precision Oncology. “So, very low on normal, but very high on diseased.” The new study applies that idea specifically to cervical cancer.

Looking beyond tumor averages

The researchers analyzed gene-expression data from 304 primary cervical cancers and 7,597 healthy tissue samples, initially identifying 30 cell-surface proteins that were significantly more highly expressed in cervical cancer.

But they did not stop with a broad comparison between cancer and healthy tissue. They also compared tumors with the specific normal cervical tissue from which different forms of the cancer arise.

That distinction matters because cervical cancer is not a single, uniform disease. Major subtypes include squamous cell carcinoma and adenocarcinoma, which arise from different tissues and have distinct biological characteristics.

The closer analysis produced different pictures for each of the three targets.

MSLN showed the broadest potential, remaining strongly elevated when tumors were compared with both normal ectocervical and endocervical tissue.

TROP-2 initially also looked like a broadly promising target. Although it was detected across the cervical tumors, it was not elevated compared with normal ectocervical tissue. It was substantially higher than in normal endocervical tissue, suggesting it could be more useful as a target in cervical adenocarcinoma rather than cervical cancer overall.

LIV-1 provided perhaps the clearest example of why researchers may need to look beyond averages. It did not rank among the top 30 targets when the tumors were considered as a single group. When the investigators looked at individual tumors, however, they found 14—about 5% of the cohort—with particularly high LIV-1 expression.

“You might identify antigens which are upregulated in some patients but downregulated in others,” Barth said.

For Barth, the LIV-1 result was also a reminder of the limitations of any broad screening approach. A target that appears unremarkable when researchers average results across hundreds of tumors could still be highly relevant to a smaller group of patients.

Putting the targets to the test

The investigators next asked whether targeting MSLN, TROP-2, and LIV-1 could actually kill cervical cancer cells.

They created experimental ADCs against each protein. ADCs pair an antibody that recognizes a target on a cancer cell with a potent cancer-killing drug, with the goal of delivering the drug more directly to malignant cells.

All three experimental ADCs bound to cervical cancer cells and produced dose-dependent cell killing, although their activity varied among the cell lines tested. TROP-2-targeted ADCs, for example, were particularly active in the squamous cell carcinoma-derived CaSki and SiHa cell lines and also showed activity in adenocarcinoma-derived HeLa cells.

LIV-1-targeted treatment likewise showed stronger activity in some cell lines than others, broadly reflecting the variable expression seen in the computational analysis.

“The findings of our transcriptomic studies [are] confirming this for cervical cancer, and our in vitro activity studies are confirming that you can use them to selectively kill cervical cancer tumor cell lines,” Barth said.

Toward more personalized target selection

Together, the findings suggest a more refined way to search for therapeutic targets: identify proteins that are elevated in tumors, compare them with the appropriate normal tissue, and then look for smaller groups of patients whose tumors may express a particular target at especially high levels.

That last step could be particularly important for precision oncology. Patients diagnosed with the same type of cancer may have very different levels of a particular target—and therefore may not be equally likely to benefit from a therapy directed against it.

“If you…have a screening tool in place that would allow you to identify the patients with the best upregulated cell surface antigens, that’s the precision medicine approach you would need to identify the best patients responding to any type of immunotherapy,” Barth said.

The study remains preclinical. The computational analysis measured messenger RNA rather than the amount of target protein actually present on tumor cells, and the therapeutic experiments were performed in cell lines rather than patients. Barth said moving from transcriptomic analysis toward protein-level data will be important for making target selection more predictive.

Still, the cervical cancer study offers a proof of principle for looking beyond whether a tumor is simply “positive” or “negative” for a particular target. By considering how strongly a target is expressed, what normal tissue it is being compared with, and how expression varies from patient to patient, researchers may be able to more precisely identify who is most likely to benefit from targeted immunotherapies.

The post Multi-Layered Screening Identifies Potential ADC Targets in Cervical Cancer appeared first on Inside Precision Medicine.

About 50% of people with heart failure have a heart that can still pump normally but becomes stiff and loses its ability to relax, limiting how much blood it can fill with. Known as heart failure with preserved ejection fraction (HFpEF), this condition can cause breathlessness, fatigue, and reduced ability to exercise. 

“This type of heart failure remains one of the most challenging forms of heart disease to treat,” said Joseph Burgoyne, PhD, senior lecturer at King’s College London and senior author of the study. “Despite its growing burden, treatment options remain limited because the disease is complex and varies considerably between patients.”  

In recent years, urolithin A has attracted growing interest because of its links to healthy aging and mitochondrial function. Our bodies naturally produce urolithin A when gut microbes break down ellagitannins, a group of compounds found in pomegranates and walnuts. However, not everyone produces the same amount of urolithin A, largely because of differences in gut microbiome composition. 

Burgoyne and colleagues found that urolithin A activates the PKGIα protein, which plays an important role in maintaining blood vessel function and helping the heart muscle relax. In animal models, treatment with urolithin A improved measures of heart function by up to 80% compared with controls. The compound was able to reduce fibrosis and improve the ability of heart tissue to relax, while preventing heart muscle cells from becoming enlarged. 

Similar results were seen in engineered human heart tissue closely mimicking the structure and function of human heart muscle, with urolithin A treatment significantly improving tissue relaxation.

“Our findings identify a completely new therapeutic target and show that urolithin A can activate this pathway to improve heart relaxation and reduce disease severity,” said Burgoyne. “This raises the exciting possibility of developing new treatments that improve clinical outcomes and quality of life for people living with the condition.”

Urolithin A has already been evaluated in clinical trials, where it showed a favorable safety profile. This could make it a promising candidate for further research and translation into a potential treatment for HFpEF, addressing a significant and long-standing challenge in cardiovascular medicine. 

“This type of heart failure is becoming increasingly common as populations age and rates of obesity and diabetes rise,” said Burgoyne. “While there isn’t enough evidence to suggest that people should eat pomegranates to treat heart failure, these findings raise the possibility that dietary approaches that enhance urolithin A production may help alleviate this condition.”  

The post Heart Failure Treatment May Benefit from Pomegranate and Walnut Compound appeared first on Inside Precision Medicine.

“One of the clinical challenges in managing patients with pacemakers is the need for generator replacement procedures when the battery depletes, which involves reoperation to replace it,” said Daniel Modaff, MD, cardiac electrophysiologist at UW Hospital and Clinics. “I look forward to a world in which we can implant a single device that will last a patient’s lifetime, and this is a big step closer to realizing this dream.”

For decades, the standard of care has been the transvenous pacemaker, a battery-powered device implanted near the collarbone with leads threaded through a vein into the heart. Over the past decade, however, clinics have increasingly adopted leadless intracardiac pacemakers that are implanted directly inside the heart. These devices can speed recovery, reduce certain complications, and remove the need for a chest implant.

The main drawback is the battery, which accounts for more than half of the device’s size and weight and typically lasts just 7–10 years. When the battery is empty, the pacemaker is often left inside the heart as a new one is implanted, because surgical removal can be difficult and carries additional risks. This can be particularly problematic for younger patients who may need multiple pacemaker replacements over their lifetimes. 

Although researchers have long been looking for alternatives to power these pacemakers, none could yet produce enough energy. Modaff and colleagues designed a nanogenerator that harvests energy from oscillators, each made of a pair of oppositely charged electrode plates. As the heart beats, the motion brings the plates together and pulls them apart, generating an electrical charge that can either power the pacemaker directly or be stored in a small capacitor. 

“We had to think about how to balance stability and flexibility so it could oscillate millions and millions of times but maintain the desired mechanical behavior,” said Pengfei Chen, PhD, postdoctoral scholar in materials science and engineering at UW–Madison. “We had to optimize the placement and width of every wire, and the thickness of every electrode plate and substrate.”

Laboratory tests showed that the nanogenerator could generate enough energy to operate the pacemaker, outperforming previous miniaturized solutions. The researchers then implanted the device in a pig for one month, where it successfully provided cardiac stimulation without causing additional adverse reactions compared to conventional battery-powered pacemakers. 

“For a device like this, it’s not just about producing energy,” said Xudong Wang, PhD, professor of materials science and engineering at UW-Madison. “You need to get enough power in a small enough volume. With our technology, we achieved a power output density an order of magnitude higher than previous nanogenerators.”

The oscillator’s simple design makes it relatively inexpensive to produce while also providing the mechanical robustness needed to potentially last a patient’s lifetime. However, several engineering challenges remain before the device can advance to clinical trials. 

In the pig’s heart, the nanogenerator produced less energy than it did in laboratory tests. The softer tissue dampened its movement, while the heart’s complex motion prevented the oscillator from moving in the straight up-and-down pattern that produced its maximum output under laboratory conditions. 

“We want to figure out how to transfer the more irregular movement of the heart into this mechanical oscillation efficiently,” said Wang. “This will lead to our goal by demonstrating sufficient and stable energy generation from hearts in vivo.” 

As the researchers address these challenges and refine the pacemaker’s design, they hope to lay the groundwork for a new generation of self-powered cardiac devices that could eliminate the need for battery replacement. 

“From a translational standpoint, a reliable self-sustaining power source gives device developers greater freedom to design smaller implants with enhanced diagnostic and therapeutic capabilities,” said Eric Schmuck, PhD, research assistant professor at the Center for Biomedical Swine Research and Innovation at UW–Madison. “As we continue to move toward smarter, more personalized cardiac care, technologies that harvest energy directly from the body could play a critical role in bringing these innovations from the laboratory to the patient.”

The post Heartbeat-Powered Pacemaker Could Last a Patient’s Lifetime appeared first on Inside Precision Medicine.

“We expected the evidence base to be thin, but not this thin,” said Sebastián A. Cajas Ordóñez, AI researcher at MIT Critical Data. “Out of 1,357 AI devices the FDA has cleared for use in patient care, only three have been tested on whether patients actually live longer or better.”

The use of AI tools in clinical practice is growing at unprecedented speed, increasingly influencing diagnostic and treatment decisions. Radiology applications dominate the field, accounting for 78% of FDA-cleared AI devices. However, the evidence supporting their impact on patients remains limited. 

Using data from the FDA device database and the ACR Data Science Institute catalogue, the researchers conducted a systematic analysis of all FDA-cleared AI medical devices through December 2025. Out of 1,357 cleared devices, only 34 (2.5%) were linked to registered prospective trials, and only three of these evaluated patient-centered outcomes such as death rates, hospital readmissions, and quality of life. 

Under the FDA’s 510(k) pathway, a new medical device can be cleared if it demonstrates “substantial equivalence” to an existing device. According to the study authors, this can create a chain effect in which new devices are cleared based on their similarity to previous devices that themselves may lack rigorous clinical validation, allowing evidence gaps to widen as they pass from one generation of devices to the next. 

“Regulatory approval has outpaced clinical validation, creating an ecosystem where innovation advances without accountability,” said Cajas Ordóñez. “The finding that only 0.2% of cleared devices have undergone evaluation for patient-centered outcomes reveals a profound validation gap and points to the need for evidence standards capable of keeping pace with the speed of regulatory clearance.”

The analysis also found that most of the few studies conducted took place in highly resourced healthcare systems and excluded key patient subgroups, including pregnant women, people over 75, and non-English speakers. Subgroup analyses were also rarely conducted, leaving it unclear how these AI medical devices perform across diverse populations. Because FDA clearance is often used internationally as a benchmark for adoption, the researchers warn that under-validated AI tools could be introduced into low- and middle-income countries, where resources for independent clinical validation may be limited.

Based on these findings, the scientists propose a roadmap for strengthening the clinical validation of AI medical devices. This includes mandatory prospective studies conducted in real-world clinical settings, as well as post-clearance requirements for multicenter trials with patient-centered endpoints and prespecified subgroup analyses.

“The central issue in clinical AI is not whether algorithms can classify images or predict risk; it is whether they tangibly improve patient health,” said Cajas Ordóñez. “Without systematic reform, the gap between algorithmic capability and clinical evidence will continue to widen.”

The post Nearly All FDA-Cleared AI Medical Devices Lack Evidence of Patient Benefit appeared first on Inside Precision Medicine.

“This work changes how we think about rhabdomyosarcoma,” said Sam Behjati, co-senior author from the University of Cambridge. “Rather than a single, abnormal gene, we’ve shown that there is an overarching cell state of aggressive disease that defies conventional classification systems. Understanding this shared biology could help identify children who need more intense treatment to improve their survival.”

Rhabdomyosarcoma is a pediatric soft tissue cancer that is typified by abnormal skeletal muscle differentiation. Outcomes can vary by age, disease site, and whether the tumor has spread, but the strongest prognostic indicator is a rearrangement in the FOXO1 gene, which is usually partnered with PAX3 or PAX7.

The resulting gene fusion becomes an oncogenic transcription factor that disrupts muscle cell development and is associated with poor prognosis. However, some patients with fusion-negative tumors also have poor outcomes.

Behjati and team investigated the reasons for this in 16 children with rhabdomyosarcoma that represented the disease spectrum in terms of fusion status, histological subtypes (alveolar vs embryonal), stage, and anatomical site of the primary tumor. These included four lethal fusion-positive cases, four lethal fusion-negative cases, and eight non-lethal fusion-negative cases.

Using single-cell mRNA sequencing, nuclear RNA sequencing, an assay for transposase-accessible chromatin, and single-cell spatial transcriptomics, the researchers found that cancer cells from patients with lethal disease converge on a common cell state with a shared transcriptional landscape, irrespective of fusion status.

The researchers report in Cancer Research that “lethal fusion-negative, non-alveolar tumors did not resemble embryonal tumours with good outcomes, but instead, they bore a striking similarity to fusion-positive tumors.”

They added: “This suggests that aggressive behavior in [rhabdomyosarcoma] may be better understood, at least in part, as a transcriptional cell state rather than solely as a consequence of a specific initiating genotype. In this framework, fusion-positive disease and a subset of clinically aggressive fusion-negative tumors may reach a common downstream program through distinct upstream molecular routes.”

Behjati and colleagues say this explains why some fusion-negative tumors behave more aggressively than would be expected from their conventional molecular classification.

The researchers also investigated whether lethal fusion-negative and fusion-positive rhabdomyosarcoma harbor overlapping or distinct molecular features that could be used as therapeutic targets. They found that the already known targets GPC3 and FGFR4 were preferentially expressed by non-lethal and lethal cells, respectively. In addition, neural genes, including GABRB3 and KCNH2, were particularly elevated in fusion-positive and lethal, fusion-negative disease.

The authors say the findings have potential clinical significance if validated in larger prospective studies, as they could be used to improve risk stratification by identifying apparently fusion-negative tumors that harbor a high-risk transcriptional program and may therefore warrant closer monitoring or intensified therapy.

They concluded: “In the wider context of emerging cancer cell atlases, the significance of our findings is to reveal a cancer cell state, as represented in mRNA, that transcends conventional prognostic boundaries, even in a cancer type that is as molecularly and clinically thoroughly characterized as [rhabdomyosarcoma]. Our approach of focusing quantitative molecular analyses on disease patterns may reveal similar findings in other cancer types.”

The post Aggressive Rhabdomyosarcoma Defined by Cell State Rather than Gene Fusion appeared first on Inside Precision Medicine.

“Our results show that gut bacteria can convert components in food into biologically active molecules that influence important bodily functions,” said Andrei L. Kleschyov, senior researcher at Karolinska Institutet and first author of the study.

Kleschyov and colleagues showed that certain gut bacteria can convert nitrate and iron obtained from our diet into dinitrosyl iron complexes (DNICs), which are then absorbed and transported through various organs throughout the body, primarily the liver and kidneys. In particular, the bacteria produced DNICs using nitrate found in vegetables like beetroot and spinach, and non-heme iron found in foods including beans, whole grains, and green vegetables. 

DNICs are naturally occurring molecules that act as a transport vehicle for nitric oxide, a volatile gas that plays an important role in human health but breaks down quickly unless it is bound to a more stable form of storage. Previous work by Kleschyov’s team established that DNICs can serve this critical function. Meanwhile, other studies have linked DNICs to lower blood pressure, protection against oxidative stress, modulation of inflammation, and reduced tissue damage during a heart attack. 

Experiments in mice and human tissue samples identified the presence of DNICs in various tissues. However, these molecules were completely absent in germ-free mice, suggesting that the gut microbiota may be crucial for their formation.

At the same time, increasing DNIC levels improved several health markers in mouse models of both cardiovascular and metabolic disease. The researchers achieved similar effects by either introducing dietary supplements of nitrate and iron or directly administering synthetically produced DNICs.

“Among other things, we observed lower blood pressure and improved vascular function, better blood sugar control, and reduced fat accumulation in the liver,” said Mattias Carlström, PhD, professor of cardiorenal physiology at Karolinska Institutet. “The results help to explain why a diet rich in vegetables, which contain both nitrate and iron, is linked to a lower risk of several diseases.”

While these findings point to a potential new link between diet, gut microbes, and human health, the process has yet to be studied in humans. Next, the scientists plan to develop methods for measuring DNIC levels in people and investigate how these molecules are produced and transported through the body, as well as their specific physiological effects. These studies could ultimately reveal whether changes to diet or the gut microbiota can alter DNIC levels and, in turn, help prevent cardiometabolic disease. 

The post Gut Bacteria Reveal Link Between Diet and Cardiometabolic Health appeared first on Inside Precision Medicine.

The work, which is being developed in partnership with Fujifilm, is still at an early stage, but may provide a more flexible and better-tolerated way to get circular RNA and other genetic therapies into cells, an important requirement for RNA medicines designed to work for longer and be dosed on a regular basis.

“The success of mRNA vaccines has shown the transformative power of RNA medicines, and the field is now moving toward next-generation modalities such as circular RNA, which offers greater stability and more durable protein expression than linear mRNA,” wrote the investigators in Cell Biomaterials.

“A key hurdle is delivery: conventional lipid nanoparticles are optimized for linear mRNA and struggle with the rigid, closed-loop structure of circular RNA.”

Most standard lipid nanoparticles were created to fit and carry relatively flexible, linear mRNA, not circular RNA. FL0445 has three lipid branches around a central charged group. The authors propose that this branching prevents the lipids from packing too tightly, creating a less rigid internal structure. FL0445 also contains a helper lipid called DOPE (dioleoylphosphatidylethanolamine), which may help the RNA to escape into the target cell.

In this study, the researchers tested the efficacy of FL0445 at delivering a therapeutic load in human cell lines and in a mouse model. In this case, they used a glucagon-like peptide (GLP)-1 encoding circular RNA to treat obese mice with glucose intolerance.

FL0445 delivered a range of RNA types and sizes of molecules efficiently in cells, often more effectively than comparison formulations. It caused less activation of inflammatory pathways than other commonly used delivery particles and also seemed to use a different, cholesterol-dependent route than other methods, which may help it to reach its target better and avoid being targeted by the parts of the cell that break down unwanted material.

In mice, FL0445 was particularly effective after injection under the skin or into muscle. It also produced lower levels of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha, than some comparator particles.

“These data support our hypothesis that introducing a branched scaffold into the hydrophobic lipid tail generates a more flexible internal lipid nanoparticle architecture, enabling efficient accommodation of rigid payloads such as circular RNA while improving both delivery performance and safety,” the authors wrote.

However, they do acknowledge that more work is needed to develop this work further; the delivery mechanism remains partly unresolved, and repeated-dose safety, manufacturing, and performance in larger animals and people still need to be established.

The post Special Lipid Nanoparticle Shows Promise for Delivering RNA Therapies appeared first on Inside Precision Medicine.

Cardiomyopathy encompasses a group of diseases that impair the heart’s ability to pump blood. These conditions cause the heart to become enlarged, with weak and irregular heartbeats, increasing the risk of heart failure. Although cardiomyopathy affects around 30 million people worldwide, treatment options remain limited and are often highly invasive.

“Genetic forms of cardiomyopathy are a major reason why children need heart transplants,” said James McNamara, PhD, honorary fellow and team leader at Murdoch Children’s Research Institute (MCRI). “If this success translates to patients, the gene therapy could become the first targeted treatment for a range of inherited heart diseases, offering families a future without progressive heart failure or the eventual need for a transplant.”

“Additionally, this would spare children from invasive surgical or catheter-based procedures, long-term medication, and needing implantable devices like pacemakers and defibrillators to repair or manage their heart defect.” 

The gene therapy is designed to deliver a healthy copy of the ALPK3 gene, which plays an important role in the development and maintenance of muscle tissue. Variants in ALPK3 can cause severe cardiomyopathy, with affected children often requiring lifelong medication, repeated surgical procedures, and, when the disease progresses, heart transplantation. 

McNamara’s team first developed a mouse model of ALPK3 that replicated the early-onset and severity seen in children with the same mutations. In these mice, the gene therapy successfully repaired the structural abnormalities in diseased heart cells and restored pumping function to their failing hearts. 

“Strikingly, we also showed that the therapy not only prevented cardiomyopathy in newborn mice but also completely reversed the disease in adult mice,” said McNamara. “This was a huge result, suggesting to us that the heart heavily depends on ALPK3.”

The researchers then recreated the disease in human heart organoids grown from patient stem cells. Treatment with the gene therapy successfully restored their contractile function. 

“These mini hearts in a dish had the same type of cardiomyopathy as the patients with ALPK3 gene variants,” said McNamara. “We replaced the faulty copies of ALPK3 with the healthy version and completely restored normal beat strength and rhythm in the mini hearts.”

Next, the scientists investigated whether the gene therapy could be used to target other genetic forms of cardiomyopathy. Using Geneformer, an AI model developed by collaborators at Gladstone Institutes, they predicted that patients with mutations in the MYH7 and TTN genes were likely to benefit from this treatment—with TTN variants alone accounting for up to a quarter of all cases of dilated cardiomyopathy. 

“Importantly, the TTN gene itself is just too big to replace using our current gene therapy technologies, so this gene therapy could be used to treat a range of cardiomyopathies, including those with no current treatments,” said McNamara. “Variations in TTN are the most common genetic cause of dilated cardiomyopathy, so this therapy could really address a large unmet need for patients worldwide.”

The broader potential of the gene therapy remains to be explored, including experimental confirmation of which of the predicted MYH7 and TTN variants can be treated with this approach and to what extent. 

“Further safety studies are needed before we start human trials, but we have been blown away by the preclinical results,” said Enzo Porrello, PhD, professor at MCRI and director of the Melbourne node of the Novo Nordisk Foundation Centre for Stem Cell Medicine. “We are now seeking commercial partners to take this gene therapy into human clinical trials.”

The post Gene Therapy Could Reverse Genetic Heart Disease, Spare Children from Transplants  appeared first on Inside Precision Medicine.