STAT+: How a four-month FDA delay forced a small biotech company to close its doors

In February, a small biotech company called Kezar Life Sciences reached a breakthrough with the Food and Drug Administration, agreeing to a plan for a clinical trial it hoped could lead to the approval of its treatment for a rare, debilitating liver disease called autoimmune hepatitis. The problem: The agreement came four months too late.

The meeting to discuss trial design, a critical step in the drug development process, had been scheduled for last October. But the FDA abruptly canceled it without explanation. The company could no longer proceed as planned and, without clarity from regulators, its path forward was unclear. Kezar’s investors wanted out, and the biotech was forced to start the process of winding down.

It laid off most of its staff of about 60 people. Then, it auctioned off its lab equipment and sold much of its office furniture, except for the table and chairs in one conference room it kept in case the company got its meeting with FDA staff.

Last week — after the meeting and the breakthrough happened — the company said it would be sold. Kezar hopes the buyer, Aurinia Pharmaceuticals, will take the drug forward, though how quickly that can happen, if at all, is not guaranteed.

It’s also not clear why Kezar’s initial meeting was canceled. But to CEO Chris Kirk, the chain of events fits a pattern over the past year in which volatility at the FDA — including staff departures and decision-making seen as inconsistent — has ricocheted across the industry, impacting drugmakers. Those impacts can fall disproportionately on small companies, which, unlike major drugmakers, often operate on one financing to the next. 

“In my career, I’ve often not agreed with what the FDA has said, but I’ve at least relied on their consistency,” said Kirk, who’s worked in biotech for more than two decades. “That doesn’t appear to be what’s happening now. It feels more stochastic and maybe even capricious, what’s going on at the FDA. And this isn’t good for patients. It’s definitely not good for the biotech ecosystem as a whole.”

Continue to STAT+ to read the full story…

StockWatch: Price War Dampens Lilly Surge After Oral GLP-1 Wins FDA Nod

Eli Lilly (NYSE: LLY) won the approval it sought when the FDA authorized the company’s oral obesity drug Foundayo™ (orforglipron), but the pharma giant’s post-approval stock bounce was short-lived.

Lilly shares rose 4% from $919.77 to $954.52 on the day of the announcement. But the momentum reversed into a 2% loss to $935.58 on Thursday, and for one important reason beyond simply the overall market decline triggered by investors losing confidence in a speedy end to the Iran war.

Investors (as reflected in analysts’ mixed observations) appeared divided on how quickly Lilly can generate sales this year for Foundayo, a small molecule glucagon-like peptide-1 (GLP-1) receptor agonist. That division results from the competition shaping up on the drug’s price with obesity arch-rival Novo Nordisk (shares traded on Nasdaq Copenhagen as NOVO-B; ADRs traded on NYSE as NVO).

Novo Nordisk got a jump on Lilly in the oral obesity drug front in December when the Danish biotech giant won FDA approval for oral Wegovy® (semaglutide), a once-daily 25 mg tablet indicated for chronic weight management. Analysts consider oral Wegovy sales to have started strong, with total prescriptions reaching 577,000 and 52,000 filled during the week ending March 20.

Lilly is expected to make Foundayo available directly to patients through its LillyDirect direct-to-consumer services and support platform starting Monday. There, a starting dose of 0.8 mg is being priced at $149/month, rising to $199/month for 2.5 mg, $299/month for the 5.5 mg and 9 mg doses, and up to $349/month for the highest doses of 14.5 mg and 17.2 mg. However, high-dose patients will automatically receive the $299/month price on their first purchases and keep it if they refill their prescription within 45 days of their previous prescription.

Patients paying through commercial insurance plans will be eligible for discounts that reduce Foundayo’s out-of-pocket cost to patients for 1-, 2-, or 3-month prescription fills to $5 a month.

“A positive surprise is that the approval was for a tablet formulation, which is less expensive to manufacture” than the capsule versions studied by Lilly during clinical trials, David Risinger, a senior managing director and senior research analyst covering diversified biopharmaceuticals at Leerink Partners, shared in a research note.

Lilly told Risinger that it conducted a bioequivalence study comparing capsules to tablets, which, according to the company, can be manufactured more efficiently than capsules and use less active pharmaceutical ingredient. The high dose studied in Lilly’s Phase III trials of orforglipron, 36 mg, corresponds to the highest capsule dose of 17.2 mg.

Price competition

Lilly has sought to price its oral obesity drug competitively with Novo Nordisk’s oral Wegovy, which starts at $149/month for the lowest dose of 1.5 mg, then rises to $199/month for the 4 mg dose, with new patients paying $149/month through August 31. Prices rise to $299/month for 9 mg and 25 mg doses.

However, patients who sign up for a 12-month subscription to oral Wegovy through Novo Nordisk’s telemedicine partner-providers enjoy a $50 discount that brings their monthly cost down to $249. And commercial insurance patients who agree to local pharmacy pickup with a savings offer can pay as little as $25/month, subject to a maximum savings of $100/month.

The price competition explains why buyers of securities for themselves or clients—the “buy side” in Wall Street jargon—have lowered their 2026 forecasts for Foundayo sales by more than half, from about $4 billion to less than $2 billion, Trung Huynh, an analyst with RBC Capital Markets, wrote in a research note. Huynh cited a consensus of analysts which is projecting approximately $1.6 billion in 2026 sales, though a Reuters spot check of investment brokerages found a range for this year’s projected sales of $1.5 billion to $2.8 billion.

“Although there have been headwinds on pricing erosion in the GLP-1 space, we believe there is substantial upside with the expected Medicare Part D expansion later this year,” Huynh added. The expansion of sales to the Medicare Part D program would cap patient copays at $50 per month.

Huynh and RBC Capital have projected Foundayo will reach peak-year sales of $36 billion—14% above the $31.68 billion racked up by last year’s best-selling prescription drug, the multi-indication cancer immunotherapy blockbuster Keytruda® (pembrolizumab) marketed by Merck & Co. (NYSE: MRK).

The highest peak sales forecast comes from Citi Research, where Geoff Meacham, PhD, the firm’s head of healthcare research and a managing director specializing in U.S. pharma and biotech research, has projected more than $40 billion. At the low end, a consensus of analysts surveyed by Bloomberg News expects Foundayo peak sales to reach $18 billion by 2030.

$50M upfront

Both ends are a far, far cry from the $50 million upfront that Lilly paid in 2018 to license orforglipron, then called OWL833, from Chugai Pharmaceutical, which discovered the drug and is owned by Roche Holding (SIX Swiss Exchange: ROP and RO; OTCQX: RHHBY). Lilly also agreed to pay Chugai up to $390 million in potential payments tied to achieving milestones.

At the time, OWL833 was deemed Phase I ready for clinical studies in type 2 diabetes—the indication for which Lilly markets its GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist tirzepatide as Mounjaro®, and Novo Nordisk markets its GLP-1 receptor agonist semaglutide as Ozempic®.

“Overall, we continue to believe that injectable anti-obesity medications will retain the majority of market share (roughly 80%, based on our estimates) in the United States due to the high potency of injectables coupled with a more elevated U.S. BMI population,” Andy T. Hsieh, PhD, a partner and biotechnology analyst with William Blair, wrote in a research note.

Beyond competitive pricing and lower manufacturing costs, Lilly has emphasized a convenience advantage over oral Wegovy—starting with its public announcement of the approval, whose headline referred to Foundayo as “the only GLP-1 pill for weight loss that can be taken any time of day without food or water restrictions.”

While Foundayo can be taken morning, afternoon, or evening, oral Wegovy, by contrast, requires patients to take the pill with up to 4 ounces of water on an empty stomach as soon as they wake up, then fast for 30 minutes before they can eat or drink.

“Accordingly, we expect Foundayo to blunt the uptake of oral Wegovy upon its availability (starting on April 6), though oral Wegovy retains a pricing advantage,” Hsieh concluded.

Huynh of RBC Capital agreed, citing a survey by his firm of about 200 patients, payers, and prescribers: “Our recent survey indicated that Foundayo would be a preferred oral option amongst patients since it has no dosing restrictions.”

Not so, Novo Nordisk CEO Maziar (Mike) Doustdar told CNBC last month: “People are really interested because it’s the most efficacious pill right now in the market.”

Novo Nordisk cites efficacy

Novo Nordisk sought to reinforce that message via an announcement trumpeting that its 25 mg dose of oral Wegovy showed “significantly” greater mean weight loss than the 36 mg dose of Foundayo, according to a population-adjusted indirect treatment comparison using data from two clinical trials:

  • OASIS 4 (NCT05564117), a 307-patient randomized study which evaluated once-daily oral Wegovy 25 mg in overweight or obese adults with at least one self-reported unsuccessful dietary effort to lose body weight, to measure their percentage change in body weight and whether it was ≥5% at the end of treatment at week 64.
  • ATTAIN-1 (NCT05869903), a 72-week, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron (6 mg, 12 mg, and 36 mg) as monotherapy vs. placebo in 3,127 adults with obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, OSA, or cardiovascular disease, who did not have diabetes.

Novo Nordisk plans to present details of its study, called ORION, at the Obesity Medicine Association’s annual Obesity Medicine 2026 conference, set for April 10-12 in San Diego.

News of the FDA approval for Foundayo caused Novo Nordisk shares to dip 0.1% Wednesday from DKK 231.15 ($35.65) to DKK 230.90 ($35.61). But the shares finished the trading week climbing nearly 3% Thursday to DKK 236.90 ($36.53).

U.S. and major European markets were closed on Friday in observance of Good Friday.

Foundayo is the fifth prescription drug to be authorized under the FDA’s Commissioner’s National Priority Voucher program, through which the agency awards vouchers to drug developers whose work will address a health crisis in the United States, deliver more innovative cures, address unmet public health needs, and increase domestic drug manufacturing as a national security issue.

The approval came nearly 10 months ahead of Foundayo’s target decision date of January 20, 2027, under the PDUFA (Prescription Drug User Fee Act) program, and just 50 days after Lilly filed a new drug application (NDA) for the oral obesity drug with the FDA.

Leaders and laggards

  • Inovio Pharmaceuticals (NASDAQ: INO) shares nosedived 35% from $1.74 to $1.13 Thursday after the developer of DNA therapies to treat and prevent HPV-related diseases, cancer, and infectious diseases announced that it priced at $1.40 a share an underwritten public offering of 12.5 million shares of common stock, plus accompanying Series A and Series B warrants, each series enabling potential purchase of up to 12.5 million shares (or pre-funded warrants in lieu thereof). The dilutive offering is projected to raise $17.5 million in gross proceeds—$16 million in net proceeds, rising to $18.4 million if underwriter Piper Sandler exercises in full its 30-day option to purchase up to 1.875 million additional shares and all Series A and Series B warrants (1.875 million shares each series). Net proceeds are intended to fund a potential commercial launch of INO-3107, a recurrent respiratory papillomatosis candidate under FDA review with a target decision date of October 30, as well as a confirmatory trial for INO-3107 if required, pipeline development, and general corporate purposes.
  • Oric Pharmaceuticals (NASDAQ: ORIC) shares tumbled 19% from $12.67 to $7.47 Wednesday after the cancer drug developer said it will advance rinzimetostat (ORIC-944) into a 600-patient Phase III trial (Himalaya-1 ) after generating positive data from its Phase Ib trial (NCT05413421) assessing rinzimetostat plus the Bayer (XETRA: BAYN)-marketed Nubeqa® (darolutamide) as a once-daily treatment for metastatic castration-resistant prostate cancer (mCRPC) in patients previously treated with abiraterone acetate (abiraterone). At a median follow-up of 4.9 months, the combination showed radiographic progression-free survival (rPFS) rates of 93% at 3 months, 84% at 4 months, and 84% at 5 months—rates consistent, Oric said, with the competitor PRC2 inhibitor currently in Phase III in post-abiraterone mCRPC patients and superior to available standard-of-care therapies showing rPFS rates of approximately 60% to 75%. Also, 47% of patients (7/15) achieved a PSA50 response, with 33% (5/15) confirmed, while 71% of patients (10/14) achieving >50% circulating tumor (ctDNA) reduction. Jefferies analyst Maury Raycroft, PhD, reported that some investors viewed rinzimetstat as “a better fit strategically” with Johnson & Johnson (NYSE: JNJ)-marketed Erleada® (apalutamide).
  • Sangamo Therapeutics (NASDAQ: SGMO) shares climbed 20% from 25 cents to 30 cents between Tuesday and Thursday after the genetic medicine developer said it expects to complete this summer its rolling Biologics License Application (BLA) submission seeking FDA approval for isaralgagene civaparvovec (ST-920), a gene therapy candidate being developed to treat Fabry disease, subject to securing adequate additional funding, while continuing business development discussions for a potential Fabry commercialization agreement. Sangamo said it is advancing the chemistry, manufacturing, and controls (CMC) module ahead of completion of the rolling BLA submission. Since launching its rolling BLA submission in December under an Accelerated Approval pathway, Sangamo has submitted preclinical and clinical modules, as well as submitted its antibody assay companion diagnostic, designed to screen patients for eligibility with isaralgagene civaparvovec, to the FDA’s Center for Devices and Radiological Health (CDRH), seeking Premarket Approval (PMA).

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Social cognitive deficits and altered multi-brain dynamics during problem-solving in heroin abstainers: An fNIRS hyperscanning study

Despite extensive research on the neurobiology of addiction, little is known about how repeated drug use and withdrawal are related to social functioning impairments in humans, a highly social species. This obscures the broader societal impact of drug addiction and limits treatment efficacy. This study examined social cognitive impairment and its multi-brain neural underpinnings during socially interactive problem-solving in heroin use disorder (HUD), and further explored their co-occurrence with protracted withdrawal symptoms.

Low Birthweight Increases Risk of Early Stroke

Research led by the University of Gothenburg in Sweden suggests that low birthweight is a risk factor for having a stroke in younger adulthood.

In a study including just under 800,000 people, the investigators found that risk for early stroke events was 18-23% higher in men and women who had a birth weight under the median level than those with a higher birth weight.

Around 795,000 people in the U.S. have a stroke each year. Although it can affect people of any age, it is much more common in older individuals with estimates of prevalence suggesting that 0.9% of 18–44 year olds have strokes versus 3.8% of those in the 45–64 year age group and 7.7% of people aged 65 and over.

Low birth weight has been previously linked to an increased risk for stroke in several studies. Researchers think that low birth weight is an indicator of exposure to an adverse environment in the womb that may adversely affect the cardiovascular system of the fetus in a way that increases stroke risk—for example, by increasing the risk of high blood pressure.

Over the last 10-15 years, stroke prevalence has stayed the same in older adults but has gone up by 14-16% in 18-64 year-olds. Lina Lilja, a doctoral student at the University of Gothenburg, and colleagues aimed to investigate whether low birth weight increased the risk of stroke in younger adults.

They included 420,173 men and 348,758 women from Sweden who were born between 1973 and 1982 and followed up from birth until 2022. The researchers collected data on birth weight, gestational age, and body mass index in young adulthood, as well as information on first stroke and the type of stroke.

Overall, 2252 first stroke events were recorded at an average age of 36 years. Of these, 1624 were ischemic stroke (average age 37 years) and 588 were intracerebral hemorrhage (average age 33 years).

The results, which will be presented at the European Congress on Obesity in Istanbul later this year, showed that birth weight below the median (3.5kg) increased the risk for all stroke by 21%. The rates of stroke were slightly higher in men with a low birthweight at 23% versus women with a low birthweight at 18%.

Notably, gestational age at birth and young adult body mass index were not linked to stroke risk in this study.

The post Low Birthweight Increases Risk of Early Stroke appeared first on Inside Precision Medicine.

Pancreatic Cancer Development Driven by NADPH Disruption

Researchers at the University of Michigan have uncovered metabolic pathways that explain how pancreatic cells transition from acinar-to-ductal metaplasia to pancreatic ductal adenocarcinoma (PDAC). The study, published in Nature Metabolism, detailed on how reduced production of a molecule central to biosynthesis and oxidative stress control called NADPH alters cellular conditions to favor cancer progression. By examining precancerous pancreatic lesions, the team found that disruptions in enzymes responsible for NADPH production increase oxidative stress, accelerating the formation of lesions and, in some cases, the progression to PDAC.

“We know a lot about how pancreatic tumors behave and look, but we don’t know how they become cancerous,” said lead author Megan Radyk, PhD, a former postdoc in the lab of Costas Lyssiotis, PhD, at the University of Michigan and now an assistant professor at Roswell Park Comprehensive Cancer Center. “We wanted to learn about what metabolic changes happen before you get an established tumor.”

PDAC is the most common form of pancreatic cancer and has a low five-year survival rate. The disease develops through a stepwise process that begins with acinar-to-ductal metaplasia (ADM), a reversible state in which pancreatic cells respond to injury or inflammation by adopting a duct-like phenotype. Under normal conditions, these cells can revert to their original state. However, in the presence of oncogenic KRAS mutations, this process is disrupted, leading to persistent ADM and progression to pancreatic intraepithelial neoplasia (PanIN), which can ultimately become PDAC.

NADPH’s normal role is in maintaining cellular homeostasis. It supports the synthesis of lipids, cholesterol, and nucleotides, and it aids antioxidant systems that regulate reactive oxygen species (ROS). Under normal conditions, NADPH helps neutralize ROS, preventing cellular damage. The current study, however, demonstrated that lower levels of NADPH impair antioxidant defenses, leading to increased ROS and lipid peroxidation, which in turn promote the formation of precancerous lesions.

The researchers identified two NADPH-producing enzymes for their work: glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1). Both enzymes support the production of the appropriate levels of NADPH needed for biosynthesis and ROS regulation.

Using a multimodal approach involving RNA sequencing, metabolomics, and mouse models with oncogenic KRAS mutations, the Michigan team studied how the loss of these two enzymes affects pancreatic tissue. They observed that deficiency in either G6PD or ME1 increased ROS levels and accelerated the formation of ADM and pancreatic intraepithelial neoplasia (PanIN) lesions. Antioxidant treatments, including glutathione and N-acetyl cysteine, reduced lesion formation, further bolstering the current understanding of the role of oxidative stress in early tumorigenesis. The team achieved similar results when these methods were applied to human pancreatic tissue samples.

But results from later in the study showed that the two enzymes played distinct roles in the later stages of PDAC. While they both contributed to early lesion formation, only the loss of ME1 promoted progression to PDAC. This suggests that although both enzymes regulate NADPH and oxidative stress, they have distinct roles in later metabolic demands of cancer cells.

The study builds on prior research showing that KRAS mutations drive metabolic reprogramming and ROS production in pancreatic cells. Previous work has also indicated that antioxidant pathways, including those regulated by NRF2, are activated during tumor initiation.

Clinically, these findings suggest that targeting metabolic pathways involved in NADPH production could provide a strategy to intercept pancreatic cancer before it fully develops. Measuring levels of G6PD, ME1, or related metabolites could also serve as biomarkers to identify patients at higher risk of lesions progressing to cancer.

“Our study can help the search for new biomarkers that can intercept pancreatic cancer before it progresses,” the researchers wrote.

Future research will focus on identifying additional enzymes that regulate NADPH levels and determining how these pathways can be targeted safely. The researchers also plan to study whether patients with mutations in G6PD, ME1, or related pathways have an increased risk of pancreatic disease.

The post Pancreatic Cancer Development Driven by NADPH Disruption appeared first on Inside Precision Medicine.

Injectable Microgel Developed to Reduce Bleeding in Infants Undergoing Surgery

Biomedical researchers headed by a team at the Lampe Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, have developed an injectable microgel to help reduce bleeding in infants who require surgical care. Tests in an animal model showed that the hemostatic microgels, known as B-knob-triggered microgels (BK-TriGs), reduced bleeding by at least 50%.

Research lead Ashley Brown, PhD, who is the Lampe Distinguished Professor of Biomedical Engineering, is co-corresponding author of the team’s published paper in Science Advances, titled “Hemostatic B-knob-triggered microgels (BK-TriGs) to address bleeding in neonates.” In their paper the team concluded “This study highlights the potential of BK-TriGs, designed for neonatal-specific clotting mechanisms, to address the heightened bleeding and thrombosis risks in neonates, who face 4.4 times higher postsurgery mortality … Our findings support BK-TriGs as a promising approach for improving hemostasis in neonates, offering a tailored, effective solution for this vulnerable patient population.”

When adults cut themselves, a multi-step process called hemostasis stops the bleeding from the injured blood vessel. But hemostasis in infants is different from hemostasis in adults. This difference can be problematic if infants require surgery to address significant medical problems. In surgeries, neonatal patients normally receive blood from adult donors to compensate for blood lost during the operation. “Current treatments rely on transfusing adult blood products, which may cause complications resulting from structural and functional differences between neonatal and adult fibrinogen,” the authors wrote. “… these transfusions pose serious safety concerns by increasing morbidity, prolonging intensive care unit stays, and elevating posttransfusion thrombosis risks in neonates.”

Brown noted, “… if you give adult blood to an infant, the difference in adult hemostasis versus infant hemostasis can lead to too much clotting. That can increase the likelihood of thrombosis, where blood clots form in the lungs or elsewhere and put the baby at risk … “My research team has done a lot of work on surgery-related bleeding in newborns, and we wanted to develop a therapeutic intervention that would reduce bleeding and—by extension—reduce the need for infants to receive adult blood transfusions during surgery.”

The scientists have now reported on their development of a material called B-knob triggered microgels (BK-TriGs). “Fibrin is the main clotting protein in human blood,” Brown explains. “There is a short amino acid sequence called a ‘B peptide’ that links together fibrin molecules to create blood clots where they are needed—and these B peptides play a particularly important role in hemostasis for infants. The BK-TriGs are engineered particles that are studded with those B peptides.”

The particles can absorb water and become squishy hydrogels, which mimic the mechanical properties of natural platelets in a way that maximizes the ability of the B peptides to create fibrin networks and stanch bleeding. “Functionalized with a fibrin hole b–specific peptide, BK-TriGs enhance clot density and resistance to degradation,” the team noted.

The researchers first tested the BK-TriGs by using microfluidic devices that allowed them to conduct in vitro testing to see how the microgels affected clotting in blood plasma from human adults and infants. “In vitro studies using neonatal platelet-poor plasma (PPP) showed that at an optimal concentration, BK-TriGs increased clot density by more than 100% and improved stability by reducing fibrinolysis,” they wrote in summary. “Under flow conditions BK-TriGs promoted robust clot formation compared to plasma-only controls.” Brown noted, “We found that BK-TriGs worked better at improving blood clotting in infant plasma than in adult plasma, which was what we expected to see.”

To further test the efficacy of the BK-TriGs, the researchers worked with lab mice that were genetically engineered to not make fibrinogen, the precursor to fibrin. This allowed the researchers to first introduce infant fibrinogen into the lab mice so that the mice exhibit a form of hemostasis similar to infants. “This innovative model enabled the evaluation of BK-TriGs in a setting that replicates key aspects of neonatal fibrinogen polymerization and fibrinolytic sensitivity, providing preliminary insights into their potential clinical utility.”

Brown added, “We found that the BK-TriGs outperformed any of the other options we tested at reducing blood loss. Specifically, the BK-TriGs reduced blood loss by 50-60% compared to the control group.”

The authors further stated, “The findings highlight the potential of BK-TriGs as a promising synthetic platelet-mimetic approach for enhancing clot density and stability, particularly in neonatal plasma where traditional blood products may pose risks … A fibrin-targeted approach like BK-TriGs, which enhances clot formation without introducing systemic thrombotic risk, may offer a safer alternative to adult fibrinogen transfusions.”

Next steps for the work are to see how BK-TriGs compare to other hemostatic therapeutics that are on the market, either on their own or when used in conjunction with BK-TriGs. “The results we’re reporting here are exciting, but we are still far removed from clinical use,” Brown, acknowledged. “We need to make sure there are no unforeseen risks associated with blood clotting.” The team also commented, “Expanding this research to include different clinical bleeding scenarios will be essential to advancing these materials toward therapeutic applications.”

“This is particularly relevant in neonates, where the most severe bleeding complications often arise in critical sites such as the gastrointestinal tract and the brain,” Brown continued, “But if we do find BK-TriGs are safe and effective, we’re optimistic this could be a cost-effective way to make surgery safer for infants. Manufacturing the BK-TriG particles would be relatively inexpensive—certainly in comparison to blood products.”

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How an Alzheimer’s Risk Gene Rewires the Brain Decades Before Symptoms

For millions of people worldwide, carrying the APOE4 gene variant means a significantly higher risk of developing Alzheimer’s disease. Yet one of the biggest unanswered questions has been when, and how, that risk begins to take hold in the brain.

New research from the Gladstone Institutes, published in Nature Aging, suggests that the effects of APOE4 emerge far earlier than previously understood. The study shows that subtle but important changes in brain activity occur long before memory loss begins, offering a potential window for early intervention.

Early changes in a seemingly healthy brain

Alzheimer’s disease is typically diagnosed after cognitive symptoms appear, but growing evidence suggests that the disease process begins decades earlier. The new study adds to this picture by demonstrating that brain circuits in young individuals carrying APOE4 are already functioning differently.

We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages, ” said Misha Zilberter, PhD, principal staff research scientist at Gladstone and senior author of the study.

The researchers observed increased neuronal activity in the hippocampus, a brain region essential for learning and memory. Similar patterns of hyperactivity have been reported in human APOE4 carriers, even before clinical symptoms arise.

According to the scientists, this suggests that Alzheimer’s risk is not simply a matter of late-stage degeneration, but may instead involve long-term changes in how brain circuits are wired and function.

Smaller neurons, stronger signals

To understand what drives this early hyperactivity, the team examined individual brain cells. They found that neurons in key regions of the hippocampus were physically smaller in APOE4 carriers compared to those with the more common, lower-risk APOE3 variant.

While this might seem like a minor structural difference, it has functional consequences. Smaller neurons are more easily activated, meaning they fire more readily in response to stimuli. This heightened sensitivity can lead to persistent hyperactivity within neural circuits.

Over time, this imbalance may place stress on the brain and contribute to the gradual decline seen in Alzheimer’s disease.

A surprising source of dysfunction

For years, researchers believed that APOE4’s effects were primarily driven by astrocytes, support cells in the brain that produce most of the APOE protein. However, the new findings challenge this assumption.

The team discovered that the disruptive effects on brain activity were instead linked to APOE4 produced directly by neurons themselves. When APOE4 was removed from neurons, their size and activity returned to normal. Removing it from astrocytes, by contrast, had little effect.

This shift in understanding refocuses attention on neurons as key drivers of early disease processes, rather than passive victims of surrounding dysfunction.

A reversible pathway—and a new target

Perhaps the most striking finding of the study is that these early changes may not be permanent.

The researchers identified a protein called Nell2 as a central player in the process. Levels of Nell2 were elevated in APOE4 neurons and appeared to drive both the reduction in cell size and the increase in neuronal activity.

By reducing Nell2 levels in adult mice, the team was able to restore normal neuron structure and function—even after the changes had already occurred.

“What’s exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level,” said Yadong Huang, co-senior author of the study. “That tells us the damage is not irreversible […].”

This raises the possibility of developing therapies that target Nell2, potentially slowing or preventing disease progression in individuals at high genetic risk.

Implications for early intervention

APOE4 is present in roughly one in four people and in the majority of Alzheimer’s patients. Despite this, current treatments largely focus on late-stage symptoms rather than early prevention.

The new findings suggest that intervening earlier, before cognitive decline begins, could be key. If brain circuit changes can be detected and corrected at an early stage, it may be possible to delay or even prevent the onset of Alzheimer’s disease.

The study also highlights the importance of understanding how genetic risk translates into functional changes in the brain. Rather than acting as a simple risk marker, APOE4 appears to actively reshape neural activity over time.

A shift in perspective

More broadly, the work reflects a growing shift in Alzheimer’s research, from focusing solely on hallmark features such as amyloid plaques and tau tangles to examining earlier, subtler changes in brain function.

By identifying a concrete pathway linking genetic risk to altered brain activity, the study provides a clearer framework for understanding how the disease develops.

“This study is a big breakthrough for the field of Alzheimer’s research,” Huang said. “It opens the door to a better understanding of how APOE4 alters the function of neurons at a young age to increase risk of cognitive decline, and to the development of therapies that could block the detrimental effects of APOE4 early on.”

While the findings are based on mouse models, they align closely with observations in humans and offer a strong foundation for future research. The next steps will involve determining whether targeting Nell2 or similar pathways can produce similar benefits in human patients.

If successful, such approaches could transform how Alzheimer’s disease is treated, not as an inevitable consequence of aging, but as a process that can be detected early and potentially reversed.

The post How an Alzheimer’s Risk Gene Rewires the Brain Decades Before Symptoms appeared first on Inside Precision Medicine.

Epigenetic Strategy Restores Tumor Suppressor in Acute Myeloid Leukemia Models

Scientists from The Jackson Laboratory (JAX) and their collaborators elsewhere have found a potential way to treat cases of acute myeloid leukemia that involves turning a key cancer fighting gene back on. Besides potentially treating AML without harsh chemotherapy regimens, their work also highlights a promising strategy for studying gene-silencing mechanisms in other diseases. Full details of the study, which was done in mice, are available in a paper published in Science Translational Medicine titled “Epigenetic reactivation of the tumor suppressor ZBTB7A by KDM4 inhibition in human acute myeloid leukemia.”

Normally, tumor suppressor genes work to prevent cells from becoming cancerous. But in cancers like AML, some of these genes are switched off epigenetically. These changes to gene activity are difficult to track because standard DNA sequencing technologies are designed to find mutated DNA. “If we can identify which genes have been silenced and understand how to turn them back on, that could open up entirely new therapeutic possibilities,” said Eric Wang, PhD, an assistant professor JAX who led the research. “Instead of only trying to kill these cells, we may be able to restore the mechanisms that normally keep them under control.”

Though scientists have made great strides in developing therapies for AML, prognosis for the disease is still relatively poor. Part of the challenge is that AML cells remain in an immature, stem cell-like state. According to the paper, Wang and his team developed a tool that combines fluorescence in situ hybridization and flow cytometry with CRISPR gene editing technology to map gene activity in cells. They used the tool, called FISHnCRISP, to identify a tumor-suppressing gene called ZBTB7A that is silenced in AML patients. By restoring ZBTB7A expression, the scientists forced the cancer cells into a state where they grew less aggressively.

Digging into the details, AML cells produce a longer version of ZBTB7A’s regulatory tail, that contains sites that attract a protein called ZFP36L2, which reduces the gene’s activity. Additionally, a family of enzymes known as KDM4 modify how DNA is packaged inside AML cells, which effectively silences ZBTB7A expression. Data from experiments in mice with AML showed that when KDM4 enzymes were blocked, ZBTB7A regained its expression, reducing leukemia burden while leaving normal blood formation largely unaffected.

Importantly, “there are drug candidates out there to inhibit KDM4, and in our study we just repurposed one of them to treat AML cells,” Wang said. “We won’t know unless we test it in clinical trials, but this approach could be better than chemotherapy, because we showed it’s not toxic at all to normal blood cells.” 

Future studies will focus on refining the approach and determining whether it might be combined with existing treatments. The team plans to test an experimental drug that targets KDM4, which is currently being tested in a clinical trial for solid tumors. 

“We demonstrated that downregulating ZBTB7A causes this hyperinflammatory state that promotes cancer growth” and “now, we’re proposing this epigenetic approach to force AML cells to differentiate into white blood cells that eventually undergo cell death,” Wang said. “We could potentially translate our research into an early phase clinical trial more readily than developing a whole new compound from scratch.” 

The post Epigenetic Strategy Restores Tumor Suppressor in Acute Myeloid Leukemia Models appeared first on GEN – Genetic Engineering and Biotechnology News.

STAT+: NIH would get $5 billion cut under Trump’s 2027 budget, but Congress unlikely to go along

The White House is asking Congress to cut $5 billion from the National Institutes of Health and to downsize the number of its institutes and centers from 27 to 22 — a plan that is expected to receive a chilly reception from lawmakers from both parties. 

The president’s fiscal year 2027 budget request, released Friday, asks for $41 billion for the NIH and eliminates the National Center for Complementary and Integrative Health, the Fogarty International Center, and the National Institute on Minority Health and Health Disparities. The 2027 budget also proposes consolidating two institutes focused on research on drug and alcohol abuse into a new entity called the National Institute of Substance Use and Addiction Research, as well as relocating the National Institute of Environmental Health Sciences into the Centers for Disease Control and Prevention. 

The White House proposal also asks Congress to slash the budget for the Advanced Research Projects (ARPA-H), which funds cutting-edge science, from its current $1.5 billion to $945 million.

Continue to STAT+ to read the full story…

Four things we’d need to put data centers in space

MIT Technology Review Explains: Let our writers untangle the complex, messy world of technology to help you understand what’s coming next. You can read more from the series here.

In January, Elon Musk’s SpaceX filed an application with the US Federal Communications Commission to launch up to one million data centers into Earth’s orbit. The goal? To fully unleash the potential of AI without triggering an environmental crisis on Earth. But could it work?

SpaceX is the latest in a string of high-tech companies extolling the potential of orbital computing infrastructure. Last year, Amazon founder Jeff Bezos said that the tech industry will move toward large-scale computing in space. Google has plans to loft data-crunching satellites, aiming to launch a test constellation of 80 as early as next year. And last November Starcloud, a startup based in Washington State, launched a satellite fitted with a high-performance Nvidia H100 GPU, marking the first orbital test of an advanced AI chip. The company envisions orbiting data centers as large as those on Earth by 2030.

Proponents believe that putting data centers in space makes sense. The current AI boom is straining energy grids and adding to the demand for water, which is needed to cool the computers. Communities in the vicinity of large-scale data centers worry about increasing prices for those resources as a result of the growing demand, among other issues.

In space, advocates say, the water and energy problems would be solved. In constantly illuminated sun-synchronous orbits, space-borne data centers would have uninterrupted access to solar power. At the same time, the excess heat they produce would be easily expelled into the cold vacuum of space. And with the cost of space launches decreasing, and mega-rockets such as SpaceX’s Starship promising to push prices even lower, there could be a point at which moving the world’s data centers into space makes sound business sense. Detractors, on the other hand, tell a different story and point to a variety of technological hurdles, though some say it’s possible they may be surmountable in the not-so-distant future. Here are four of the must-haves we’d need to make space-based data centers a reality. 

A way to carry away heat 

AI data centers produce a lot of heat. Space might seem like a great place to dispel that heat without using up massive amounts of water. But it’s not so simple. To get the power needed to run 24-7, a space-based data center would have to be in a constantly illuminated orbit, circling the planet from pole to pole, and never hide in Earth’s shadow. And in that orbit, the temperature of the equipment would never drop below 80 °C, which is way too hot for electronics to operate safely in the long term. 

Getting the heat out of such a system is surprisingly challenging. “Thermal management and cooling in space is generally a huge problem,” says Lilly Eichinger, CEO of the Austrian space tech startup Satellives.

On Earth, heat dissipates mostly through the natural process of convection, which relies on the movement of gases and liquids like air and water. In the vacuum of space, heat has to be removed through the far less efficient process of radiation. Safely removing the heat produced by the computers, as well as what’s absorbed from the sun, requires large radiative surfaces. The bulkier the satellite, the harder it is to send all the heat inside it out into space.

But Yves Durand, former director of technology at the European aerospace giant Thales Alenia Space, says that technology already exists to tackle the problem.

The company previously developed a system for large telecommunications satellites that can pipe refrigerant fluid through a network of tubing using a mechanical pump, ultimately transferring heat from within a spacecraft to radiators on the exterior. Durand led a 2024 feasibility study on space-based data centers, which found that although challenges exist, it should be possible for Europe to put gigawatt-scale data centers (on par with the largest Earthbound facilities) into orbit before 2050. These would be considerably larger than those envisioned by SpaceX, featuring solar arrays hundreds of meters in size—larger than the International Space Station.

Computer chips that can withstand a radiation onslaught

The space around Earth is constantly battered by cosmic particles and lashed by solar radiation. On Earth’s surface, humans and their electronic devices are protected from this corrosive soup of charged particles by the planet’s atmosphere and magnetosphere. But the farther away from Earth you venture, the weaker that protection becomes. Studies show that aircraft crews have a higher risk of developing cancer because of their frequent exposure to high radiation at cruising altitude, where the atmosphere is thin and less protective.

Electronics in space are at risk of three types of problems caused by high radiation levels, says Ken Mai, a principal systems scientist in electrical and computer engineering at Carnegie Mellon University. Phenomena known as single-event upsets can cause bit flips and corrupt stored data when charged particles hit chips and memory devices. Over time, electronics in space accumulate damage from ionizing radiation that degrades their performance. And sometimes a charged particle can strike the component in a way that physically displaces atoms on the chip, creating permanent damage, Mai explains.

Traditionally, computers launched to space had to undergo years of testing and were specifically designed to withstand the intense radiation present in Earth’s orbit. These space-hardened electronics are much more expensive, though, and their performance is also years behind the state-of-the-art devices for Earth-based computing. Launching conventional chips is a gamble. But Durand says cutting-edge computer chips use technologies that are by default more resistant to radiation than past systems. And in mid-March, Nvidia touted hardware, including a new GPU, that is “bringing AI compute to orbital data centers.” 

Nvidia’s head of edge AI marketing, Chen Su, told MIT Technology Review, that “Nvidia systems are inherently commercial off the shelf, with radiation resilience achieved at the system level rather than through radiation‑hardened silicon alone.” He added that satellite makers increase the chips’ resiliency with the help of shielding, advanced software for error detection, and architectures that combine the consumer-grade devices with bespoke, hardened technologies.

Still, Mai says that the data-crunching chips are only one issue. The data centers would also need memory and storage devices, both of which are vulnerable to damage by excessive radiation. And operators would need the ability to swap things out or adapt when issues arise. The feasibility and affordability of using robots or astronaut missions for maintenance is a major question mark hanging over the idea of large-scale orbiting data centers.

“You not only need to throw up a data center to space that meets your current needs; you need redundancy, extra parts, and reconfigurability, so when stuff breaks, you can just change your configuration and continue working,” says Mai. “It’s a very challenging problem because on one hand you have free energy and power in space, but there are a lot of disadvantages. It’s quite possible that those problems will outweigh the advantages that you get from putting a data center into space.”

In addition to the need for regular maintenance, there’s also the potential for catastrophic loss. During periods of intense space weather, satellites can be flooded with enough radiation to kill all their electronics. The sun has just passed the most active phase of its 11-year cycle with relatively little impact on satellites. Still, experts warn that since the space age began, the planet has not experienced the worst the sun is capable of. Many doubt whether the low-cost new space systems that dominate Earth’s orbits today are prepared for that.

A plan to dodge space debris

Both large-scale orbiting data centers such as those envisioned by Thales Alenia Space and the mega-constellations of smaller satellites as proposed by SpaceX give a headache to space sustainability experts. The space around Earth is already quite crowded with satellites. Starlink satellites alone perform hundreds of thousands of collision avoidance maneuvers every year to dodge debris and other spacecraft. The more stuff in space, the higher the likelihood of a devastating collision that would clutter the orbit with thousands of dangerous fragments.

Large structures with hundreds of square meters of solar arrays would quickly suffer damage from small pieces of space debris and meteorites, which would over time degrade the performance of their solar panels and create more debris in orbit. Operating one million satellites in low Earth orbit, the region of space at the altitude of up to 2,000 kilometers, might be impossible to do safely unless all satellites in that area are part of the same network so they can communicate effectively to maneuver around each other, Greg Vialle, the founder of the orbital recycling startup Lunexus Space, told MIT Technology Review.

“You can fit roughly four to five thousand satellites in one orbital shell,” Vialle says. “If you count all the shells in low Earth orbit, you get to a number of around 240,000 satellites maximum.”

And spacecraft must be able to pass each other at a safe distance to avoid collisions, he says. 

“You also need to be able to get stuff up to higher orbits and back down to de-orbit,” he adds. “So you need to have gaps of at least 10 kilometers between the satellites to do that safely. Mega-constellations like Starlink can be packed more tightly because the satellites communicate with each other. But you can’t have one million satellites around Earth unless it’s a monopoly.”

On top of that, Starlink would likely want to regularly upgrade its orbiting data centers with more modern technology. Replacing a million satellites perhaps every five years would mean even more orbital traffic—and it could increase the rate of debris reentry into Earth’s atmosphere from around three or four pieces of junk a day to about one every three minutes, according to a group of astronomers who filed objections against SpaceX’s FCC application. Some scientists are concerned that reentering debris could damage the ozone layer and alter Earth’s thermal balance

Economical launch and assembly

The longer hardware survives in orbit, the better the return on investment. But for orbital data centers to make economic sense, companies will have to find a relatively cheap way to get that hardware in orbit. SpaceX is betting on its upcoming Starship mega-rocket, which will be able to carry up to six times as much payload as the current workhorse, Falcon 9. The Thales Alenia Space study concluded that if Europe were to build its own orbital data centers, it would have to develop a similarly potent launcher. 

But launch is only part of the equation. A large-scale orbital data center won’t fit in a rocket—even a mega-rocket. It will need to be assembled in orbit. And that will likely require advanced robotic systems that do not exist yet. Various companies have conducted Earth-based tests with precursors of such systems, but they are still far from real-world use.

Durand says that in the short term, smaller-scale data centers are likely to establish themselves as an integral part of the orbital infrastructure, by processing images from Earth-observing satellites directly in space without having to send them to Earth. That would be a huge help for companies selling insights from space, as many of these data sets are extremely large, and competition for opportunities to downlink them to Earth for processing via ground stations is growing.

“The good thing with orbital data centers is that you can start with small servers and gradually increase and build up larger data centers,” says Durand. “You can use modularity. You can learn little by little and gradually develop industrial capacity in space. We have all the technology, and the demand for space-based data processing infrastructure is huge, so it makes sense to think about it.”

Smaller facilities probably won’t do much to offset the strain that terrestrial data centers are placing on the planet’s water and electricity, though. That vision of the future might take decades to come to fruition, some critics think—if it even gets off the ground at all.