<![CDATA[AXS-05 for Alzheimer disease agitation nears FDA decision date. ]]>
CRISPR Base Editing Repairs Hard-to-Treat Cystic Fibrosis Mutation in Cell Models
Affecting an estimated 100,000 people globally, cystic fibrosis (CF) cases stem from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the past several decades, scientists have successfully engineered various small-molecule therapies that lessen the severity of the disease. However there are still treatment challenges. Now, data from a new study in a cell model demonstrates that a gene therapy can successfully repair an “untreatable” mutation associated with a particularly severe form of the disease. Details of the potential therapy are published in a new Science Translational Medicine paper titled “Functional correction of the untreatable CFTR 1717-IG>A mutation through mRNA- and sgRNA-optimized base editing.”
Many current therapies benefit patients with the most common disease-associated mutation, F508del. However they often have little effect on patients who harbor other types of mutations. For example, some patients have a mutation named 1717-1G>A, which is relatively common but doesn’t have any approved therapies due to being a splicing mutation that results in little to no protein production. In fact, “about 10% of people with CF do not qualify for any of the available CFTR modulator therapies, particularly those people with severe splicing mutations that result in frameshifts and the formation of premature termination codons.”
The 1717-1G>A mutation is the target of the therapy described in the paper, which was written by scientists from the University of Trento and their collaborators elsewhere. Specifically, the team developed an “adenine base editing strategy to efficiently correct the 1717-1G>A mutation,” they wrote in Science Translational Medicine. “By harnessing the SpRY- ABE9 system, which we delivered as optimized RNAs for both the base editor and single guide RNA (sgRNA), we achieved functional correction in patient-derived models.”
Furthermore, the scientists note that they opted to use base editing rather than strategies like base editing because it has the advantage of “typically higher nucleotide modification efficiencies and a streamlined system requiring only the editor and an sgRNA” and because it has been used in other CF studies.
Using their ABE9 base editor and modified CRISPR-Cas9 tool, the scientists report successfully editing up to 30% of target DNA in human embryonic kidney cell lines and patient-derived airway epithelial cells with minimal off-target effects. It also corrected the mutation in intestinal organoids derived from CF patients as evidenced by restored CFTR activity.
Additional studies are needed, especially in animals, to fully assess the effectiveness of potential therapy but early results are promising. Overall, the approach achieved an editing efficiency of 13%. Prior studies showed that 10% efficiency may be enough for functional recovery. The results suggest that the therapy could benefit the subset of patients whose disease is caused by 1717-1G>A.
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Heart’s Constant Beating Suppresses Tumor Growth in Cardiac Tissues
The results of a study by researchers at the International Centre for Genetic Engineering and Biotechnology (ICGEB) suggest that the heart’s constant beating may actively suppress tumor growth in cardiac tissues. The collective findings from the team’s research in mouse models and in engineered heart tissues (EHT) suggests that this is because cellular pathways in these tissues alter gene regulation in cancer cells to keep them from proliferating.
Headed by Giulio Ciucci, PhD, and Serena Zacchigna, MD, PhD, at the ICGEB Cardiovascular Biology Laboratory, the scientists say the findings shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to new cancer therapies based on mechanical stimulation. First author Ciucci, together with senior author Zacchigna and colleagues reported on their findings in Science, in a paper titled “Mechanical load inhibits cancer growth in mouse and human hearts.” In their report the authors concluded “Collectively, the data presented in this work provide evidence that mechanical load in the heart inhibits cancer cell proliferation, likely explaining the low incidence of cardiac tumors.”
Heart cancer is very rare in mammals, but as the authors noted, “The mechanisms that protect the heart remain elusive.” The adult human heart in addition has a limited capacity for self-renewal, with cardiomyocytes regenerating at roughly 1% per year. “This suggests that the same mechanisms that halt the proliferation of cardiac cells could also inhibit the growth of cancer cells in the adult heart,” the authors continued. One proposed explanation for this loss of cardiomyocyte proliferative capacity lies in the intense mechanical demands placed on heart tissues, which must continuously pump blood against significant resistance. “We hypothesized that it could similarly hamper the proliferation of cancer cells in the heart,” the investigators reported.
Using a genetically engineered mouse model, Ciucci et al. first showed that the heart is remarkably resistant to cancer-causing mutations, even when potent oncogenic changes were introduced. To understand why, the authors developed a transplantation model in which the heart’s mechanical workload could be reduced. By grafting a donor heart into the neck of a compatible mouse, they created a “mechanically unloaded” organ, one that remained perfused with blood but did not bear physiological strain. “To assess the contribution of mechanical load to the low incidence and growth of cancer in the heart, we used a model of in vivo cardiac unloading by heterotopically transplanting a donor heart into the neck of a recipient syngeneic mouse,” they explained.
![Image of lung cancer cells (in green) growing in a heart, in which cardiomyocytes are stained in red. Nuclei are stained in blue. [Ciucci et al., Science 2026]](https://www.genengnews.com/wp-content/uploads/2026/04/low-res-4-300x300.jpeg)
After injecting human cancer cells directly into the heart muscle, they compared tumor behavior in the unloaded transplanted heart versus the animal’s native, mechanically active heart. Across their experiments, Ciucci et al. found that mechanical load consistently suppressed the growth of various cancer types, while unloading the heart promoted tumor cell proliferation within cardiac tissue.
According to the study findings, mechanical forces within the tissue reshape the cancer cell genome’s regulatory landscape, influencing whether cells can proliferate. Central to this process is Nesprin-2, a protein that transmits mechanical signals from the cell surface to the nucleus. “Nesprin-2, a protein known to mediate mechanotransduction from the cytoplasm to the nucleus, emerged as a key molecule sensing mechanical forces operating in beating hearts and translating them into reduced cell proliferation,” the scientists reported.
Nesprin-2, a component of the LINC complex, senses the mechanical microenvironment of the heart and functionally alters chromatin structure and histone methylation, reducing gene activity linked to tumor cell proliferation. When Nesprin-2 was silenced in cancer cells, those cells regained the ability to grow in the mechanically active environment of the heart, forming tumors. “Silencing of Nesprin-2 in lung cancer cells prior to their implantation in the heart in vivo restored the capacity of the cells to proliferate in the presence of physiological mechanical load, resulting in the formation of large tumors,” the authors stated.
The team noted that their collective results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to new approaches to cancer therapy. “This offers fundamental insights into the biology of cell proliferation within the myocardium, and additionally, the mechanical stimuli that operate in a beating heart could be exploited for the development of a mechanical therapy for cancer.”
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New Markers of Diabetes and Heart Disease Revealed via Genetic Study in Indians
A study in 3,000 Punjabi Sikhs has identified previously unreported molecular pathways that contribute to cardiometabolic disease. Published today in PLOS Medicine, these findings highlight the benefits of including diverse participants in these types of studies, which have historically centered on individuals of European ancestry.
“Genetic mechanisms that predispose people to type 2 diabetes and cardiovascular disease remain poorly understood, partly because of a lack of sufficient data on non-European ethnic groups,” write the authors of the study, who were led by Dharambir K. Sanghera, PhD, director of the Genetic Epidemiology Laboratory at the University of Oklahoma Health Sciences Center. “Extending these evaluations to diverse cohorts is essential for gaining insights into the molecular pathways involved in disease.”
Sanghera and colleagues conducted a metabolite genome-wide association study to look for links between the human lipidome and cardiometabolic disorders in a Punjabi population originating from Northern India. Epidemiological studies have repeatedly shown that South Asians living abroad experience a higher incidence of type 2 diabetes and are more susceptible to cardiovascular disease compared to other ethnic groups. However, the exact mechanism responsible for this increased risk remains unknown and lipidomic and genome-wide data is lacking for Indian populations.
“Genome-wide studies have shown that genes influencing blood lipid metabolites are often linked to different diseases,” write the study authors. “However, most of this research has been done on people of European ancestry. Studying more diverse populations is important to better understand how these genetic pathways contribute to disease in different ethnic groups.”
The study looked at genetic influences on 516 lipids in 3,000 Punjabi Sikh individuals and then validated the results in larger cohorts, with both European and non-European ancestry, using data from UK Biobank, GeneRISK, DIAMANT, PROMIS, and other studies. After multiple rounds of testing and correction, results showed strong associations in 36 pairs of lipid metabolites and single nucleotide polymorphisms (SNPs). Among them, 33 had not been reported before, and three were confirmed to be ancestry-specific.
Further investigation identified a causal association between type 2 diabetes and the metabolite LPC O-16:0, which was paired with a genetic variant in the gene encoding for CD45, a key regulator of immune signaling. Another possible causal relationship was found with PC 38:4, a metabolite shown to protect against coronary artery disease in Indian populations that was paired with a genetic variant in an untranslated region of the FADS1/2 genes.
“Our study has discovered new metabolite markers and genes that intersect with pathways of inflammation and immuno-vascular diseases, which have not been reported in previous European studies, specifically emphasizing how immune system signaling affects metabolic health,” state the authors. “By identifying unique genetic signatures in Asian Indians, the research advocates for ancestry-specific medical approaches to address chronic immuno-vascular conditions in cardiometabolic disease. These advances could be beneficial in clinical practice, enabling effective personalized therapies and preventive strategies.”
The post New Markers of Diabetes and Heart Disease Revealed via Genetic Study in Indians appeared first on Inside Precision Medicine.
Vitamin D Linked to Lower Diabetes Risk in People with VDR Gene Variant
A genetic analysis of a large U.S. clinical trial suggests that vitamin D supplementation may reduce the risk of progression from prediabetes to type 2 diabetes, but only for those people who harbor specific variants of the vitamin D receptor gene. The study, led by researchers at Tufts University and published in JAMA Network Open, found that daily high-dose vitamin D lowered diabetes risk by 19% in participants with certain genotypes, opening the possibility of using vitamin D as a diabetes prevention strategy.
The new findings build on data from the Vitamin D and Type 2 Diabetes (D2d) clinical trial, a multi-site randomized study that enrolled more than 2,000 U.S. adults with prediabetes. Study participants were assigned to receive either 4,000 IU of vitamin D3 daily or a placebo. The subjects were then followed for a median of 2.5 years to assess progression to diabetes. The original trial did not show a statistically significant reduction in diabetes risk across all participants.
“But the D2d results raised an important question: Could vitamin D still benefit some people?” said lead author Bess Dawson-Hughes, MD, a senior scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “Diabetes has so many serious complications that develop slowly over years. If we can delay the time period that an individual will spend living with diabetes, we can stop some of those harmful side effects or lessen their severity.”
In their follow-on research, the Tufts noted that subsequent analysis of the D2d trial data showed that outcomes varied based on achieved blood levels of vitamin D in participants. The new study also found a genetic link to those who had improved outcomes.
To explore the role genetics might play, the investigators conducted a post hoc analysis of 2,098 D2d participants who consented to genetic testing. They focused on three common polymorphisms in the vitamin D receptor (VDR) gene: ApaI, BsmI, and FokI. The researchers first examined how vitamin D levels correlated with diabetes risk across genotypes, then evaluated how genetic variants influenced response to supplementation.
The data showed that the ApaI polymorphism is a key determinant of response. Participants with the AA genotype, which was about 30% of the cohort, did not experience a reduction in diabetes risk with vitamin D supplementation. By comparison, those with the AC or CC genotypes, the remaining 70% of participants, showed a 19% lower risk of developing diabetes when treated with vitamin D compared with placebo.
The biological basis for this effect is linked to the role the VDR gene plays in pancreatic β cells, where it influences insulin secretion and glucose regulation. Variations in the receptor may alter how effectively vitamin D exerts these effects, explaining why some individuals benefit from supplementation while others do not.
Earlier research has suggested there is a connection between vitamin D and diabetes risk. In earlier analyses of the D2d trial, participants who maintained higher blood levels of vitamin D experienced substantial reductions in diabetes incidence. These findings were supported by meta-analyses and observational studies, including research from the UK Biobank, which found that genetic variation in VDR could modify its activity.
“We hypothesized that VDR gene variants modify the association between achieved intratrial 25-hydroxyvitamin D (25(OH)D) level and diabetes risk and may modify the effect of vitamin D3 supplementation on the risk of developing diabetes,” the researchers wrote. 25(OH)D is the main form of vitamin D circulating in the blood.
The current study broadens knowledge on the role vitamin D can play in diabetes prevention by identifying the specific polymorphisms at play. The overlap between ApaI and BsmI variants provides further evidence of the role of VDR genetics, although the researchers noted that ApaI alone may be sufficient to identify likely responders.
“This genetic association analysis of the D2d study suggests that genetic variation in the VDR, specifically the ApaI polymorphism, is associated with diabetes risk at higher intratrial 25(OH)D levels and is associated with response to 4000 IU/d of vitamin D3 supplementation among adults with prediabetes,” the researchers wrote.
The implications for clinical care include the potential use of genetic testing to guide preventive treatment. A single test for the ApaI polymorphism could help identify patients with prediabetes who are most likely to benefit from higher-dose vitamin D supplementation.
While the results have established a link between variations in the VDR gene and diabetes development, the research noted that the study was not designed to assess the mechanisms underlying the genetic effects. Further, its sample size limited subgroup analyses by race and ethnicity.
“Our findings suggest we may eventually be able to identify which patients with prediabetes are most likely to benefit from additional vitamin D supplementation,” Dawson-Hughes said. “In principle, this could involve a single, relatively inexpensive genetic test.”
Next steps in this line of research include replicating the findings in independent cohorts and conducting prospective trials designed to test genotype-guided supplementation strategies.
The post Vitamin D Linked to Lower Diabetes Risk in People with <i>VDR</i> Gene Variant appeared first on Inside Precision Medicine.
Heart’s beat may help it beat cancer, mouse research suggests
Heart disease and cancer are the leading causes of death in the United States, but it is rare that cancer makes its way to the heart.
It’s an observation that clinicians have been grateful for, though largely unable to explain. But in a paper published Thursday in Science, researchers propose one potential explanation: The constant pressure that the organ is under from beating thousands of times a day and pushing gallons of blood creates an environment that is hostile to cancers. The study, which was conducted in mice, is preliminary, but outside experts said it points to potential new approaches for cancer treatments.
STAT+: Trump’s boosting of psychedelics, cannabis signal a new era in GOP drug policy
The days of “Just Say No,” it seems, are long gone.
Over the weekend, President Trump signed an executive order to increase the availability of certain psychedelics as treatments for mental health conditions, ordering that $50 million be spent, and that the Food and Drug Administration fast-track reviews to usher in their approval. At one point, the president joked to the motley assembly of administration officials, a former Navy SEAL, and the podcaster Joe Rogan: “Can I have some, please?”
On Wednesday, the Trump administration announced it had downgraded medical marijuana from the highest tier of controlled substances, and was pushing the Drug Enforcement Administration to do the same for recreational marijuana.
The president’s lenient tack on some mind-altering drugs ushers in a new world of right-wing drug policy. While the administration has emphasized hardline, militaristic tactics when it comes to fentanyl, its recent actions on “softer” drugs could represent a new era not just for Republican politics but also for American drug policy writ large.
“With this imminent move, we are now confronted with the most pro-drug administration in our history,” Kevin Sabet, the CEO of the anti-legalization advocacy group Smart Approaches to Marijuana, said in a statement. “Policy is now being dictated by marijuana CEOs, psychedelics investors, and podcasters in active addiction — it is a travesty and injustice to the American people of unprecedented proportions. The marijuana industry is the new Big Tobacco, and President Trump is welcoming them to the homes of families across this country with open arms.”
AI Tool Creates Designer Antibiotics
A generative AI tool for molecular design has created a new antibiotic that has shown promising preclinical results against methicillin-resistant Staphylococcus aureus (MRSA).
The SyntheMol-RL generative model, described in Molecular Systems Biology, could speed drug discovery and help in the fight against antibiotic resistance.
The algorithm uses reinforcement learning to rapidly design easily synthesizable small-molecule drug candidates from a massive chemical space of 46 billion compounds.
It created a compound that the researchers named synthecin, which was effective against MRSA wound infection in a mouse model, showing its utility for real-world drug discovery.
“We used our model to design new antibiotics, but it’s capable of so much more,” said researcher Jon Stokes, PhD, from McMaster University.
“We built it to be disease agnostic, meaning it could just as easily generate novel drug candidates for diabetes or cancer or other indications.”
The rapid spread of antibiotic resistance is a critical challenge facing modern medicine. In 2019, just under five million deaths were linked with drug-resistant bacteria and this number is expected to more than double by 2050 if the emergence of antimicrobial resistance continues to outpace the creation of new antibiotics.
Stokes and team examined whether SyntheMol-RL could identify potential antibiotics for MRSA, an infection listed by the World Health Organization as a high priority for new antibiotics.
It replaces SyntheMol, a previous incarnation that was not as effective for exploring the chemical space and was not able to optimize more than one molecular property, which is a necessity in real-world drug discovery.
The second-generation model uses reinforcement learning, which enables it to rapidly explore massive combinatorial chemical spaces with tens of billions of molecules for promising compounds that are easy to synthesize.
The researchers deployed SyntheMol-RL to identify compounds that simultaneously possessed the multiple drug-like properties of antibacterial activity against MRSA and aqueous solubility.
Next, they synthesized and experimentally tested 79 compounds designed by two variants of SyntheMol-RL and found a corresponding two and 11 potent hits.
One of these compounds, which they named synthecin, was able to fully arrest the growth of MRSA in a murine wound infection model.
“These results demonstrate that SyntheMol-RL is an effective and flexible framework for drug design applications,” the authors maintained.
They added: “SyntheMol-RL is compatible with any property predictor and combinatorial chemical space, it can be readily extended to a wide variety of drug discovery and molecular design problems.”
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How digitizers power next-generation SS-OCT systems
NEWS RELEASE: Enabling high-speed swept-source OCT with advanced data acquisition Optical coherence tomography (OCT) has become an essential tool in modern medical imaging, with swept-source OCT (SS-OCT) emerging as a leading modality because of its superior imaging speed, depth penetration, and sensitivity. By employing swept laser sources, SS-OCT enables high-resolution, real-time visualization of tissue microstructures, making…
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FDA warns device manufacturers of nitrosamine impurities that could cause cancer
The FDA Center for Devices and Radiological Health (CDRH) is warning manufacturers of drug-device combination products of the potential for nitrosamine impurities, which are classified as probable carcinogens associated with forms of cancer. The FDA did not name specific devices or kinds of devices that could be at risk in the letter it sent to…
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