Almost half of the top 100 medicines vulnerable to supply disruptions in the U.S. have at least one key starting material with a single source country, according to a new report from United States Pharmacopeia.

The United States Pharmacopeia has updated its list of products vulnerable to supply disruptions, adding drugs including Tamiflu and Trulicity after expanding its risk assessment to key starting materials.

Last year, the United States Pharmacopeia (USP) assessed medicines’ clinical importance, demand and supply chains to create a list of 100 vulnerable products. The nonprofit, which publishes a compendium of drug information each year, expanded the analysis this year to include key starting materials (KSMs). Because KSMs are used to make active ingredients, disruption to their supply can cause drug shortages.

The USP found 48 of the 100 vulnerable drugs use a KSM that is only sourced from one country. While the new analysis lacks information on where KSM supply is concentrated, the nonprofit said last year that 41% of KSMs in U.S.-approved active pharmaceutical ingredients (APIs) are only sourced from China. Another 16% of KSMs in U.S. APIs are only supplied by Indian companies. Most of the remaining 43% of KSMs are sourced from two or more countries.

The inclusion of KSM supply in the analysis affected which drugs the USP included on the latest list. The USP said the supply of more than one-quarter of the drugs on the latest list appears stable based on the finished product availability. However, the KSM analysis showed the products have “a single upstream potential point of failure,” leading the nonprofit to conclude they are vulnerable to supply disruption.

The USP named oseltamivir capsules, famotidine injection and metoprolol tartrate injection as drugs that it added to the list because of the KSM analysis. Oseltamivir, an antiviral that Roche sells as Tamiflu, and the two other drugs have “low measured shortage risk” and were not deemed vulnerable in last year’s analysis, the USP said. However, the three drugs rely on a single region for at least one of their KSMs.

None of the three products is on the FDA’s shortage list, but the presence of supply chain weaknesses led the USP to conclude they are vulnerable to supply disruption. Overall, 70 of the medicines on the list were readily available when the USP performed its analysis in February.

Those 70 products include dulaglutide, the GLP-1 receptor agonist that Eli Lilly sells as Trulicity. There is no explanation why the USP deemed dulaglutide, which was not on the previous list, to be vulnerable. The previous list included semaglutide, the GLP-1 drug that Novo Nordisk sells as Ozempic and Wegovy. The USP removed semaglutide from the latest list, reflecting the resolution of the drug’s shortage.

Pivotal findings for the off-the-shelf cell therapy surpassed William Blair’s expectations and sent Allogene Therapeutics’ stock up more than 50% in pre-market trading Monday morning.

Allogene Therapeutics’ cell therapy has aced an interim lymphoma test, clearing residual disease in 41.6% more patients compared to those in an observational arm of the pivotal trial.

The findings for the off-the-shelf experimental treatment surpassed the expectations of William Blair analysts and sent Allogene’s stock up more than 50% in pre-market trading Monday morning. If the study scores its main goal of event-free survival, the California biotech plans on using the data to request FDA approval.

The highly anticipated findings include data from 24 patients with large B cell lymphoma (LBCL), half of whom were given Allogene’s cema-cel as a consolidation therapy, designed to eliminate residual disease after initial treatment administration.

The futility analysis demonstrated a 58.3% measurable residual disease (MRD)–clearance rate among the 12 patients receiving cema-cel at 45 days compared to a 16.7% MRD-clearance rate for the 12 patients in the observation arm.

The efficacy seen in the data “nails” William Blair’s bull case scenario of 40% MRD-clearance, the firm wrote in a Monday note. The new findings also outperform previously stated expectations from Allogene’s leadership team of up to a 30% clearance difference.

Furthermore, the allogeneic CAR T was tied to a 97.7% reduction in plasma circulating tumor DNA (ctDNA), while ctDNA levels rose by 26.6% in the wait-and-watch group. Typically, higher ctDNA levels are associated with more advanced disease.

The interim findings, stemming from the Phase 2 ALPHA3 trial, also found cema-cel to be “very well-tolerated,” with zero cases of cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome (ICANS) occurring, according to Allogene.

Rates of low-grade infections were similar across treatment groups, though half of patients in the investigational arm experienced other neurologic events outside of ICANS—such as headache or dizziness—compared to only one patient in the observational cohort. That being said, all neurologic events were low-grade, with William Blair saying the events were likely related to preconditioning chemotherapy.

Overall, William Blair believes the futility analysis findings “significantly increases the probability of success in a blockbuster market opportunity.” As a first-line consolidation treatment, cema-cel could represent about a $2.5 billion to $3.5 billion market opportunity, Allogene estimates.

Looking forward, Allogene anticipates sharing interim data on ALPHA3’s primary endpoint of event-free survival in mid-2027 and a primary analysis the following year. The open-label trial is expected to recruit 220 patients across more than 60 sites.

Allogene’s approach is innovative in the fact that it elevates the use of MRD testing for lymphoma patients in hopes of ultimately reducing relapse risk. According to Allogene, ALPHA3 is the first randomized trial in LBCL evaluating whether MRD-guided intervention before relapse can eliminate residual disease.

“These early results represent an important step toward redefining first-line large B cell lymphoma management,” Allogene CEO David Chang said on a Monday investor call.

“Today, many patients are simply observed after first-line therapy, despite remaining at high risk of relapse, and by the time relapse occurs, disease may be more difficult to control,” the CEO explained, adding that he believes cema-cel has the potential to intervene earlier.

“Our mission is to unlock the transformative potential of CAR-T through our allogeneic platform,” Chang said. “At its core, that mission is about democratizing cell therapy, expanding patient access, simplifying delivery for physicians and treatment centers, and optimally moving CAR-T earlier in the treatment paradigm where it may have the greatest impact.”

About a third of patients enrolled in ALPHA3 are receiving treatment in community cancer centers, delivery that Allogene believes is conducive to broad adoption.

The licensing deal marks AbbVie’s first foray into new pain medicines, a space where Vertex currently enjoys a lead thanks to the NaV1.8 inhibitor Journavax.

AbbVie is getting in on the pain game in a deal with China’s Haisco Pharmaceutical Group that could be worth up to $715 million.

The Chinese biotech has granted the American pharma rights to multiple compounds for pain-related indications. The assets range from preclinical to Phase 1 testing in China, according to a Monday morning release.

This marks AbbVie’s first foray into new pain medicines, a space where Vertex currently enjoys a lead. The approval of Journavax last year ushered in a new era for the treatment of pain, with a novel non-opioid option in the pain signal inhibitor class of medicines. The drug specifically targets the NaV1.8 voltage-gated sodium channel that plays a critical role in generating and transmitting pain.

Eli Lilly is also working on new pain therapies, after buying SiteOne Therapeutics in May 2025 for up to $1 billion for a pipeline that includes a NaV1.8 inhibitor.

AbbVie and Haisco did not specify what type of pain medicines will be explored through the deal. Haisco has previously presented preclinical data on NaV1.8 inhibitors but also has analgesic and non-controlled opioids in its pipeline.

Haisco credited AbbVie’s neuroscience expertise as a strength of the new partnership. The pharma has an expansive migraine portfolio, including approved medicines Ubrelvy and Qulipta, while Vraylar is approved for bipolar disorder and major depressive disorder. Earlier in the pipeline, AbbVie is developing therapies for schizophrenia, Alzheimer’s disease and spinal cord injury.

In 2023, AbbVie bought Cerevel for $8.7 billion to challenge Bristol Myers Squibb in the schizophrenia space. But the key asset in that deal, emraclidine, has struggled in the clinic.

Unswayed by the Cerevel challenge, AbbVie also entered psychedelics last year with the $1.2 billion acquisition of Gilgamesh Pharmaceuticals’ bretisilocin.

As for Haisco, the Chinese biotech has been stepping up its international partnerships in an effort to expand around the world. The company licensed a chronic obstructive pulmonary disorder drug to AirNexis in January in a deal worth $108 million upfront, rising to over $1 billion with milestones and other potential payments.

Telix is Regeneron’s entry ticket into the radiopharma game, helping to better round out the company’s cancer portfolio, according to Truist Securities.

Regeneron Pharmaceuticals is joining the radiopharma race by partnering with Telix, leveraging the Australian biotech’s development engine to target multiple cancer indications.

“The collaboration brings a new leg to REGN’s robust pipeline,” Truist Securities told investors in a Sunday note. “We believe the partnership offers additional opportunities for long-term growth in solid tumors,” the analysts added, “further filling out REGN’s exposure in oncology and adding diversification to the current commercial-focused story.”

Under the terms of the agreement, announced Sunday evening, Regeneron is fronting $40 million to use Telix’s tech for four initial programs, over which the companies will split global commercialization costs and profits equally. The pharma will also have the option to add four more programs to the partnership for an additional but undisclosed upfront sum.

Telix has the option to not split costs with Regeneron for certain programs, in which case it will be eligible for up to $535 million in development and commercial milestones, plus low double-digit royalties, for that specific program. All told, if Regeneron maxes out its options for four additional programs, Telix could rack up roughly $4.3 billion in milestones. Telix is up 7% in pre-market trading Monday.

“Targeted radiopharmaceuticals represent a rapidly emerging frontier in oncology and an exciting opportunity to bring new treatment options to patients,” John Lin, senior vice president of Oncology & Antibody Technology Research at Regeneron, said in a statement.

The companies did not say what specific cancer indications they plan to work on, only revealing that they will leverage Regeneron’s antibody portfolio, including bispecifics, to address “multiple solid tumor targets.”

With the Telix partnership, Regeneron looks to join its fellow Big Pharma players in the radiopharma race. Currently in the lead is Novartis, which has two assets on the market: Lutathera, first approved in 2018 for gastroenteropancreatic neuroendocrine tumors (GEP-NET), and Pluvicto, given the FDA’s greenlight in 2022 for metastatic castration-resistant prostate cancer.

Lutathera grew 12% year-on-year in 2025 to bring in $816 million, while Pluvicto surged 42% to hit $1.99 billion in sales.

Chasing after Novartis is Eli Lilly, which in October 2023 dropped $1.4 billion to acquire Point Biopharma, followed in 2024 with a potential $1.1 billion partnership with Aktis Oncology and a $140 million bet with Radionetics Oncology. The Point purchase has been largely disappointing, though, with many assets from the deal either shelved or deprioritized following underwhelming data, according to reporting from OncologyPipeline.

Also in the race is Bristol Myers Squibb, which in December 2023 paid $4.1 billion to swallow RayzeBio and its alpha-emitter RYZ-101. Enrollment into a Phase 3 trial for the asset in GEP-NET was paused in 2024 due to supply issues. That same study is expected to hit primary completion later this year, according to a federal clinical trials database.

AstraZeneca is also playing in the radiopharma arena, buying its way into the market with a $2.4 billion acquisition of Fusion Pharmaceuticals in March 2024.

A limiting feature of many neurological therapies is the ability of molecules to cross the blood-brain barrier (BBB) from the circulatory system. Since the BBB prevents simple diffusion of materials across the divide, identifying the proteins responsible for transport is necessary for effective design of BBB-crossing therapies.

“So basically, everything in the circulating blood, if they want to have an exchange with the organ, they need to pass through this interface,” says senior author Jiefu Li, PhD, Janelia Research Campus Group Leader at the Howard Hughes Medical Institute.

Identification of the structures within blood vessels involved with the processes of molecular movement across the BBB has been somewhat elusive. However, Li and his team have developed a technique that not only identifies proteins within the luminal surface—the inner lining—of the vasculature, but also works in vivo, allowing them to track how these features change across the aging brain.

“Understanding how the blood-brain barrier works, particularly figuring out the molecular targets that you can play with to open and close the barrier, will provide new possibilities for drug delivery,” Li says.

Their work is published in Science in a paper entitled, “Luminal surface proteome of the brain vasculature uncovers blood-brain barrier regulators.”

Using mice, the team developed a proteomic profiling method that can be used not only in brain vasculature, but throughout the body. “Briefly, a lectin-conjugated peroxidase is perfused and anchored to the luminal surface of blood vessels to catalyze the biotinylation of adjacent proteins, thereby enabling subsequent protein enrichment and mass spectrometry analysis,” wrote the authors.

They tested the method in the brain, kidney and intestine, in both mice and northern tree shrew, showing functionality and applicability across organs and species.

“This will allow us to say: we know that the vasculature system is doing different things in different organs and it relies on this luminal surface, but how does that happen? What are the molecular players there?” Li says.

Using quantitative proteomics of the luminal surface—from early development through adulthood and aging—they found that over time there was a decrease in angiogenic and transport proteins. They also found an increase in proteins that increased stiffness in the vasculature.

In addition to developing this in vivo technique, the team identified two proteins that are temporally distinct in their expression while both playing a role in modulating BBB permeability. Knockouts of nitric oxide synthase Nos3 and arginine transporter Slc7a1 resulted in BBB leakage in neonates, but not adults, while genetic screens identified hyaluronidase HYAL2 as being required for maintaining BBB integrity throughout the lifespan of mice.

“What we know now is that we have two new pathways, potentially, to open the blood-brain barrier and to inform some therapeutic developments,” says Li.

Utilization of this proteomic based method in vivo both opens up new avenues of functional research across the cardiovascular system, and also provides data and a methodology for novel therapeutic targets for crossing the BBB.

“This method solves an important need but it’s also a very easy-to-use method, so everyone can use it,” Li says.

Cholera, caused by the bacterium Vibrio cholerae, remains a major global health threat. Like most bacteria, Vibrio cholerae lives under constant attack from viruses. To survive, bacteria equip themselves with antiviral immune systems. Previous work has shown that V. cholerae carries a large genetic element called a sedentary chromosomal integron (SCI). This structure contains hundreds of small mobile DNA units known as “gene cassettes” arranged in a long array, like a chain of pearls. A new study by researchers at the School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), has now shown that V. cholerae can efficiently acquire new SCI gene cassettes from extracellular DNA released by other V. cholerae strains, and non-cholera vibrio species, potentially adding to their own defense arsenals.

Research lead Melanie Blokesch, PhD, and colleagues reported on their findings in Science, in a paper titled “Competence-mediated DNA uptake diversifies Vibrio cholerae sedentary chromosomal integrons,” in which they concluded “Given the widespread presence of SCIs and the conservation of natural competence across the genus, we propose that SCIs function as genus-wide reservoirs of exchangeable protective genes.”

Bacteria often survive viral attack and environmental stress by sharing genes that enhance their defenses, the authors wrote. A “defining genomic feature” of V. cholerae is its sedentary chromosomal integron (SCI), a genetic element containing hundreds of mostly promoterless gene cassettes. While the function of many cassettes remains unknown, some do encode antiviral immune systems. “Although most cassettes encode proteins of unknown function, ~10% encode phage defense systems, suggesting that SCIs as well as mobile integrons function as reservoirs, or “biobanks,” of defense genes,” the authors continued.

However, most of these genes are located far from the start of the array and remain silent. Prevailing models proposed that cassettes could be internally reshuffled to activate them, yet no such rearrangements have been observed in the pandemic lineage of V. cholerae for decades. “Cassettes are thought to reshuffle under stress to the favorable first array position, yet the SCI in pandemic V. cholerae has remained static for more than 60 years.”

This raises a key question: if internal reshuffling is rare, how are cassette-encoded immune systems activated, and how do new cassettes enter the array at all? To address this question, a team led by Blokesch at the Laboratory of Molecular Microbiology at EPFL investigated whether the SCI might capture gene cassettes from genetic material entering the cell from the outside. “We asked whether SCI cassettes move horizontally rather than by intracellular reshuffling.”

A key feature of this process is natural competence, the ability of bacteria to take up free DNA from their surroundings. V. cholerae becomes naturally competent when it grows on chitinous surfaces, a polymer found in the shells of crustaceans that is abundant in aquatic environments.

In the laboratory, the team mimicked these conditions by growing bacteria on chitin and supplying DNA from different Vibrio cholerae strains or from other Vibrio species. They then tracked whether newly acquired gene cassettes were inserted into the first position of the SCI array.

Through their studies the team confirmed that that V. cholerae can acquire new SCI gene cassettes from extracellular DNA. Collective experimental results, the authors stated, “We show that SCI cassettes are efficiently acquired by naturally competent V. cholerae and inserted at the first SCI array position in an integrase-dependent manner. This process incorporates cassettes not only from other V. cholerae strains but also from diverse Vibrio species.”

In aquatic habitats, DNA is released when bacterial cells are killed by viruses, antimicrobial compounds, or bacterial weapons. Nearby competent bacteria can take up this DNA and incorporate selected fragments into their own SCI. “A loose comparison would be the following,” said Blokesch. “Imagine your grandmother passes away and, as a farewell gift, hands over the immunity she built up against the Spanish flu a century ago, immediately protecting you from that same virus. Wouldn’t that be amazing? This is essentially what we show that V. cholerae can do.”

The team also showed that cassettes inserted in this position are functional. Several defense systems provided protection against viruses that infect Vibrio species, known as vibriophages. They stated, “In this study, we show that SCI diversification efficiently occurs by horizontal transfer linked to the genus’s aquatic lifestyle: DNA released from lysed cells is taken up by naturally competent vibrios and integrated into the first position of the SCI array, the primary site of strong expression, where it confers resistance to phage and potentially other threat,” the wrote in summary. “Together, these results demonstrate that SCI cassettes can cross species boundaries, supporting a model in which SCIs may function as genus-wide reservoirs of exchangeable genes, including defense genes, that confer selective advantages under certain conditions.”

An important exception emerged. In the pandemic 7PET lineage of V. cholerae, the SCI appears largely static. “The SCI of 7PET V. cholerae is large but remarkably stable,” the authors noted. They propose that this reflects adaptation to a human-associated niche. “We propose that this reflects adaptation to a human-associated niche, where chitin is less abundant and competence induction—requiring growth on chitin to high cell density plus relief from catabolite repression is unlikely to occur,” they suggested. “As a result, SCI-mediated diversification may be largely inactive in pandemic strains.”

However, if pandemic strains were to encounter environmental conditions that enable SCI cassette acquisition, they could expand their antiviral defenses. Blokesch commented. “This possibility matters because vibriophage-based approaches are currently being explored to prevent cholera in endemic regions, and such evolutionary flexibility could ultimately affect how effective these strategies remain.”

In their paper the team concluded that since onset of the seventh pandemic, “… acquisition of novel and diverse, large defense-related genomic regions by 7PET strains appears to have been relatively limited. Consequently, reduced SCI-mediated diversification may lower the capacity of this lineage to rapidly evolve new defenses—an important consideration for ongoing efforts to deploy phage-based prophylaxis against cholera in endemic settings such as Bangladesh.”

The FDA in a complete response letter to Replimune maintained its original objection to the single-arm trial the biotech used to support the application for RP1.

Replimune’s stock fell nearly 20% Friday after the FDA rejected its advanced melanoma drug for the second time.

The FDA’s first rejection of RP1, an oncolytic immunotherapy also known as vusolimogene oderparepvec, in July 2025 sparked months of controversy, including an open letter from 22 researchers involved with the drug’s trials urging the agency to “re-review” its decision. Replimune resubmitted the application for the drug in October with new analyses on RP1’s mechanism of action and on how patients fared relative to prior treatment with an approved immunotherapy, a Replimune spokesperson told STAT News at the time.

The review team members for Friday’s decision were different from those who reviewed the company’s initial biologics license application, according to the FDA’s Complete Response Letter (CRL), which was published Friday. This was intended to “maintain objectivity and account for potential bias,” the agency said. Despite this, the team found the data presented was “insufficient to conclude substantial evidence of effectiveness” of RP1 in unresectable advanced cutaneous melanoma. RP1 was being proposed in combination with Bristol Myers Squibb’s Opdivo to treat the rare skin cancer.

Replimune’s use of a single-arm trial appears to be the sticking point for the FDA, which wrote in the rejection letter that it “would not recommend” seeking approval based on results from a single-arm study. The use of alternative trial designs, such as single-arm trials, has been a hot-button issue that drew many biotech onlookers to the FDA’s decision regarding RP1.

The FDA added in the letter to Replimune that its advice “has remained consistent as evidenced by our communications dating back to March 2021 and subsequent interactions.”

There appears to be a disconnect between the agency and Replimune, however, as CEO Sushil Patel expressed surprise with the initial rejection. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews,” Patel said in a statement at the time. “Additionally, we had also aligned on the design of the confirmatory study.”

Analysts had given RP1 a 50/50 chance of approval this time around.

Replimune had been seeking accelerated approval for RP1. The company is currently conducting a randomized Phase 3 trial of the immunotherapy in combination with Opdivo, with an estimated completion date of January 2029.

Novo Nordisk’s oral Wegovy has a few months’ head start on Eli Lilly’s newly approved pill. While the Indianapolis pharma has come from behind the Danish rival in the weight loss space before, last time it clearly had the better drug.

Eli Lilly announced Thursday the formal launch of obesity pill Foundayo eight days after its FDA approval. The pharma was well prepared, having stocked $1.5 billion worth of the drug back in February, and is hot to trot, already trailing rival Novo Nordisk’s oral Wegovy, which hit the market in early January after receiving approval just before Christmas.

The oral Wegovy launch was, by all accounts, a smashing success. The drug reached more than 3,000 patients in its first week, shooting up another 500% the following week, according to a Jan. 23 note from BMO Capital Markets. This greatly outpaced even the launch of Lilly’s ever-popular injectable Zepbound, which hit some 1,300 new prescriptions during its launch week in December 2023.

But Lilly isn’t one to let a competitor get in the way. Despite a two-year delay in launching Zepbound as compared with Novo’s injectable Wegovy, Lilly has emerged as the clear victor in that race, overtaking Novo in total GLP-1 sales last year and hitting a historic $1 trillion valuation along the way. The American pharma might have overtaken its Danish peer even sooner had both companies notfaced extended shortages and the GLP-1 compounding industry that grew up during that time.

But this head-to-head battle in the oral obesity space has a key difference from the rivals’ injectable contest—comparable efficacy. When it comes to Zepbound and injectable Wegovy, Lilly has a clear edge, with its drug helping patients lose 47% more weight in a head-to-head trial. For the companies’ oral options, on the other hand, Novo appears to have a leg up, achieving 16.6% weight loss at 72 weeks in a Phase 3 trial, as compared with Foundayo’s 11.2%, though no studies have directly pitted the two pills against each other.

Novo is fighting back against the market share lost on the injectable front with a new high-dose Wegovy, approved last month and launched on Tuesday. BMO analysts were not sold, however. The firm called the 7.2 mg approval “a step in the right direction” as Novo tries to “reinvigorate its commercial business,” according to a March 19 note. “Still, even with the new higher weight loss efficacy on label we see an uphill battle for the company as it fights to regain share from Lilly and grow the broader incretin market.”

But maybe Novo will be able to maintain its early lead in the oral race, given the apparent efficacy edge. Though growth has slowed, prescriptions for oral Wegovy continue to climb, jumping 3.9% this week, according to a BMO note on Friday.

Needless to say, all eyes are closely watching this duopoly in the obesity market. When it comes to price, the pills are largely the same, with both starting at $149 through self-pay options, and as low as $25 through insurance. But there are a few other differentiators beyond efficacy that might influence the race.

For one, Lilly’s Foundayo can be taken with or without food, whereas oral Wegovy must be taken on an empty stomach. And Foundayo is a small molecule while Wegovy is a peptide, which is typically harder to manufacture.

And because both companies offer injectable options, uptake of the pills could steal market share, effectively shuffling revenue around. Indeed, while oral Wegovy scripts continue to climb, injectable Wegovy continues to trend downward, with scripts falling 6.5% this week, according to BMO.

Novo will soon report initial revenue for the pill during the first quarter earnings period—the first and last quarter the company will enjoy a competitor-free market in the oral class.

But both Novo and Lilly are hopeful to reach new patients with the oral options, and that does seem to be happening. A February report from health analytics firm Truveta found that 36.1% of the 8,762 patients who had filled a prescription for oral Wegovy in its first six weeks on the market had never taken a GLP-1 medication before. Still, however, 21.1% had transitioned to the Wegovy pill from an injectable version, while 15.8% had switched from Eli Lilly’s injectable Zepbound.

For now, the stocks tell the same story. Novo’s valuation is holding steady at pre-Wegovy levels, less than one-third of its peak of $650 billion in mid-2024. Lilly, meanwhile, has climbed close to the $1 trillion mark again, after dipping below $900 billion last month for the first time since the early fall. But at this point in the oral obesity race, it’s anyone’s game.

In a new study published in Nature Communications titled, “Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks,” researchers from Flinders University in Adelaide have uncovered how hyperactive and dysregulated synaptic circuits emerge in the brain tissue of children impacted by Sanfilippo syndrome, a common form of childhood dementia.

In Australia, an estimated 1400 children currently live with childhood dementia, with hundreds of thousands of cases worldwide. Sanfilippo syndrome is a rare genetic condition that causes fatal brain damage. Children typically reach early developmental milestones before rapidly losing cognitive skills, speech, and mobility. Early symptoms often include hyperactivity and sleep disturbance.

Alterations in synaptic communication play key roles in neurodegenerative disease progression and cognitive decline. Yet few studies have explored how excitation and inhibition synaptic imbalances contribute to pediatric neurodegenerative disorders.

Cedric Bardy, PhD, professor and head of the Laboratory for Human Neurophysiology and Genetics at the South Australian Health, describes the study findings as “significant progress.” Chronic overactivity in the brain appears to be a fundamental mechanism contributing to cognitive deterioration in children with Sanfilippo syndrome.

Using human stem cell-derived cortical neurons and electrophysiology, the team demonstrated that excitatory synapses in the neurons of affected children become abnormally active during early brain development.

While these neurons initially developed and functioned normally, they became increasingly overactive over time. Brain cell networks showed bursts of intense, highly synchronized electrical activity as they matured, mirroring the hyperactivity and neurological symptoms seen in children with the condition.

“This hyperactivity offers a clear biological explanation for early behavioral changes, and it brings us closer to understanding the complex mechanisms contributing to childhood dementia,” said Bardy.

Results also demonstrated that these neurons are vulnerable to stress. When exposed to mild nutrient deprivation, excitatory synaptic abnormalities increased, suggesting that common illnesses or physiological stressors may accelerate neurological decline.

“Our research shows that disrupted synaptic communication is not simply a byproduct of degeneration. It is an early driver of the disease,” Bardy says.

Childhood Dementia Initiative CEO and founder, Megan Maack, is a co-author of the study and has been involved in guiding the project since its inception.

“This research is significant not just for Sanfilippo syndrome, but for the field of childhood dementia as a whole,” said Maack. “By identifying the precise cellular mechanisms driving the disease, we are moving towards a personalized medicine approach—the kind of targeted treatment strategy that has transformed outcomes for children with cancer.”

Researchers are now evaluating whether drugs that are already on the market for use in other conditions could be repurposed for childhood dementia. Bardy says the team has already demonstrated that these synaptic imbalances can be corrected with certain medications in the laboratory, indicating that they represent a genuine therapeutic target.

The biological connection between a pregnant woman and her developing baby—the human maternal–fetal interface—is a specialized, transient organ composed of uterine cells from the mother and fetal cells that acts as a barrier, supports fetal growth, and maintains the mother’s health. The cellular complexity of the maternal-fetal interface has limited scientists’ ability to study how healthy pregnancies develop and why complications arise. The underlying cellular, molecular, and spatial programs of the interface—which forms about a week after fertilization and lasts until birth—has remain incompletely defined.

Now, the human maternal–fetal interface has been mapped in unprecedented detail by scientists at the University of California, San Francisco (UCSF), revealing new cell types and providing insights into conditions such as preeclampsia, preterm birth, and miscarriage.

“By examining this tissue cell by cell across pregnancy, we can begin to understand both normal development and what may go wrong,” said Susan J. Fisher, PhD, professor of obstetrics, gynecology, and reproductive sciences at UCSF.

The team generated a comprehensive atlas of the human maternal–fetal interface across normal pregnancies, from early gestation to term. The researchers did this by “integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometer-resolution spatial transcriptomics and CODEX multiplex protein imaging.”

Using these tools, the researchers analyzed about 200,000 individual cells and compared them with nearly one million cells in their original positions within the uterine and placental tissue. This enabled them to identify different cell types, track how they develop, and see how they are linked to pregnancy complications.

“This work gives us a much clearer picture of this critical region than ever before,” said Jingjing Li, PhD, associate professor in UCSF’s Department of Neurology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.

This work is published in Nature in the paper, “Single-Cell Spatiotemporal Dissection of the Human Maternal–Fetal Interface.”

The atlas revealed a previously unknown maternal cell type located where fetal placental cells first enter the uterus. These cells appear to regulate how deeply placental cells invade uterine tissue, a process that is essential for establishing blood flow to the fetus. The researchers found that these cells carry a cannabinoid receptor, and exposure to cannabinoid molecules caused them to further restrict placental cell invasion.

“Population studies have linked cannabis use during pregnancy to poorer outcomes,” said Cheng Wang, PhD, a postdoctoral fellow at UCSF. “This cell type may help explain the biological basis of that association.”

To understand how complications arise, the team integrated genetic data from more than 10,000 patients. They mapped genetic risk signals for conditions including preterm birth, preeclampsia, and miscarriage onto regulatory regions of DNA that control gene activity. This approach allowed the researchers to identify the specific cell types and states most strongly associated with each condition.

The team then focused on preeclampsia, a potentially life-threatening disorder marked by sudden high blood pressure. They found that the most affected cell types are involved in remodeling the mother’s uterine blood vessels, a process required to supply adequate blood to the placenta. The findings suggest that preeclampsia may result from disrupted communication between maternal and fetal cells that normally coordinate this process.

Having established a detailed map of healthy pregnancies, the researchers plan to study complicated pregnancies to identify potential targets for treatment.