On Thursday, the federal government closes the letter-of-intent window for MAHA ELEVATE, a $100 million initiative to fund “functional or lifestyle medicine” interventions for Medicare beneficiaries. The stated goal is to test evidence-based approaches to chronic disease prevention alongside conventional care. The unstated risk is that it will open a federal funding pipeline to interventions that sound integrative but can’t survive contact with a plausibility filter.
I’m a palliative care physician. I spend my days managing pain, breathlessness, nausea, and the existential weight of serious illness. My field should be cheering this investment in whole-person care. Instead, I’m watching it with one eye on the evidence and the other on a pattern I’ve seen up close: When uncertainty is high and emotions are higher, sectarian certainty moves in fast.
There is no doubt that autologous chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of serious blood cancers. A significant proportion of advanced-stage blood cancer patients who failed to respond to previous therapies now go into remission with this treatment, with some remaining cancer-free in the long term.
However, despite their success, these immunotherapies have significant disadvantages. Although CAR T-cell therapies have essentially rescued advanced-stage patients who previously would only have been offered palliative care, serious side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) are associated with the treatment.
All seven CAR T-cell therapies approved by the U.S. Food and Drug Administration (FDA) since August 2017 are autologous cell therapies, wherein the patient’s own T cells must be extracted and genetically engineered in the lab to produce cancer-targeting CAR T cells that are reinfused into the patient to fight the cancer.
Unless they live near a major cancer center or company with the relevant expertise and lab capacity in-house, many eligible patients miss out on the therapy because the wait time is too long or the whole process is too expensive. Patients must also be admitted to the hospital to undergo lymphodepletion chemotherapy before receiving the final infusion to allow the infused cells to expand, persist, and work better.
“It’s just simply too expensive, too complex to manufacture, and has all kinds of logistical issues that translate to limited patient access,” explained Maurits Geerlings, MD, co-founder, CEO, and president of in vivo CAR T-cell therapy biotech NanoCell Therapeutics, which has offices in Pennsylvania and Utrecht.
“Also, importantly, the batch capacity in highly specialized hospitals is so limited that altogether maybe 10% of patients that are eligible effectively get access to CAR T-cell therapy in the Western world.”
Maurits Geerlings, MD Co-founder, CEO NanoCell Therapeutics
Initially, after the first ex vivo, autologous CAR T-cell therapies like Novartis’s Kymriah and Kite’s Yescarta were approved in 2017, the field looked to develop “off-the-shelf” allogeneic therapies made from donor cells that would overcome some of the issues with autologous CAR T-cell therapies.
Despite the best efforts of a number of companies and researchers, no allogeneic CAR T-cell therapies have yet reached the market, although some companies like Allogene have reached Phase II trials. This is likely due to a few factors, such as adverse events linked to the rejection of donor cells, complex engineering problems, and the small margin of benefits of allogeneic over autologous CAR T-cell therapies.
Instead, over the last couple of years, the focus of the field has moved towards developing next-generation in vivo CAR T-cell therapies. Until recently, vectors or nanoparticles that could hit T cells precisely, safely, and predictably enough in humans to justify skipping ex vivo engineering were simply not available, but this is now changing.
In vivo CAR T-cell therapy uses the patient as a bioreactor. Upon injecting an engineered treatment carried by a vector such as a lentivirus or a lipid nanoparticle (LNP), it programs the patient’s T cells to attack either the cancer or autoreactive B cells in the case of autoimmune disease.
The field is still young, but initial clinical results reported last year in multiple myeloma blood cancer by Kelonia Therapeutics and in the B cell-driven autoimmune disease systemic lupus erythematosus by MagicRNA, as well as from EsoBiotec and academic labs, are promising.
Kevin Friedman, PhD Co-founder, CEO Kelonia Therapeutics
“It’s early days, so I don’t want to overinterpret the data. It’s also only in four patients, but what we are seeing is substantially better than what ex vivo CAR T cells have shown from an efficacy perspective,” emphasized Kelonia CEO and co-founder Kevin Friedman, PhD.
Indeed, this early success seems to have prompted intense investor and big pharma interest in the field. Since March 2025, when EsoBiotec was acquired by AstraZeneca, at least four other in vivo CAR T cell biotechs have been acquired, including Capstan Therapeutics by AbbVie and Interius BioTherapeutics by Kite/Gilead.
Whether in vivo CAR T-cell therapy will truly be the future of the field remains to be seen, but its convenience, economic viability, and the fact that it is effectively an “off-the-shelf” therapy that does not require lymphodepletion make it an attractive prospect for many.
Credit: Kelonia
Lentiviral vectors: Sticking with a known quantity
Five of the seven FDA-approved autologous CAR T-cell therapies, including Kymriah, use lentiviral vectors in the lab to engineer a patient’s T cells and transform them into CAR T cells.
Many of the most advanced companies in the in vivo CAR T- cell therapy space are applying similar technologies and using lentiviral vectors to target and transform T cells, but inside the body rather than in the lab.
Kelonia, which is based in Boston, is a leader in the in vivo CAR T-cell space and has already started clinical trials with its lead candidate KLN-1010 for the treatment of patients with relapsed and refractory multiple myeloma.
“It’s essentially delivering a fully human anti-BCMA (B cell maturation antigen) CAR to T cells, to reeducate them by expressing this anti-BCMA CAR inside the body to fight their tumor cells. Just like Abecma, or Carvykti, but it’s all done inside the body,” explained Friedman.
At the American Society of Hematology Annual Meeting in December last year, the company presented early Phase I results from four patients with relapsed and treatment-resistant myeloma who were treated with KLN-1010.
Although the study was small, the results were promising, with all four patients showing 100% minimal residual disease-negative response rate at follow-up and a lower rate of side effects than approved autologous CAR T-cell therapies.
“With our data and the efficacy and the safety profile that we’re seeing, this has a real shot at getting out of the major medical centers and into the community hospitals where the patients live, so they don’t have to travel to major medical centers,” said Friedman.
“Doctors can potentially treat patients in their own community and get access to the 90% of myeloma patients who, right now, despite the profound clinical benefit that CAR T cells provide, cannot be treated.”
Ryan Larson, PhD Senior Vice President Umoja Biopharma
Umoja Biopharma is another biotech using lentiviral vectors to develop in vivo CAR T-cell therapies. “We have three different products in the clinic currently. Two of those products are in B-cell malignancies, and one of the products is in autoimmune disease. And we’re making really great progress in enrolling patients across those studies,” said Ryan Larson, PhD, senior vice president and head of research at Umoja, although the Seattle-based company has not yet released any results from its Phase I studies.
Although Umoja is using lentiviral vectors, it has built in a rapamycin-activated cytokine receptor, which essentially acts as a booster switch for the engineered T cells in cancer patients while slightly dampening the rest of the immune system.
“It allows us to deliver a controlled pro-survival signal selectively to our CAR T cells in vivo,” explained Larson. “We’re able to potentiate persistence in a controlled manner in our in vivo generated CAR T cells with this rapamycin-activated cytokine receptor to drive persistence and ongoing immune surveillance, thus driving the key durable outcomes in oncology specifically.”
The requirements for autoimmune disease patients are different from those of advanced cancer patients, with a greater focus on safety. Long-term depletion of B cells is also not ideal, with the aim being to reset the immune system by getting rid of autoreactive B cells and replacing them with healthy ones.
“You’re eliminating all of the autoreactive repertoire and replacing it with a normal B cell repertoire, thus driving, ideally, a durable response wherein those autoimmune disease patients are no longer reliant on all the various immunosuppressants that are typically used to treat autoimmune disease,” said Larson.
Kite Pharma, now owned by Gilead and headquartered in California, was a pioneer in the autologous CAR T-cell therapy space. It developed Yescarta, one of the first two autologous CAR T-cell therapies approved by the FDA to treat blood cancers in 2017. Kite recently acquired Interius BioTherapeutics, a biotech in the lentiviral in vivo CAR T-cell space, for $350 million.
Priti Hegde, PhD Senior Vice President Kite Pharma, a Gilead Company
“The reason why we moved forward with Interius was that the clinical proof of concept for lentiviral-based delivery systems is far more advanced than for LNP-based systems,” said Priti Hegde, PhD, senior vice president and global head of research at Kite. “We were really excited to see that translation of the pharmacokinetics from an ex vivo platform to an in vivo platform.”
While lentiviral vectors are arguably “tried and tested” in the CAR T-cell space, there are some disadvantages associated with using them. For example, they can be hard to produce, implying that it is expensive and challenging to scale up manufacturing.
This is something both Umoja and Kelonia seem to have addressed, however. “We actually are quite unique from a biotech perspective in that we have our own, wholly owned manufacturing facility … It’s really allowed us to have a true pipeline from an in vivo cell therapy development perspective,” said Larson. “We’re actively working in our early phase clinical trials in a manufacturing setting that we know is scalable to commercial readiness.”
Kelonia does not do all its manufacturing in-house, but Friedman said that they have worked hard to develop a system that can be scaled. “Manufacturing is complicated. We like to think that we were thoughtful about our manufacturing approach, but it’s challenging generating these particles, these complicated medicines for Phase I use. We did it, though, and we now have a very reliable and scalable manufacturing process.”
Another potential risk linked to lentiviral and other viral vectors is that there is a small but significant risk of the vector inducing unwanted mutations in the DNA of target cells.
“Viral vectors have a propensity to integrate in transcriptionally active gene regions where you don’t want to go, because that enhances the mutagenesis risk,” noted NanoCell’s Geerlings.
Taking the non-viral route
Not everyone working to develop in vivo CAR T-cell therapies is using viral vectors. The second main route that companies and researchers are following to develop these cell and gene therapies is to use mRNA encapsulated in an LNP.
Last September, Shenzhen-based Chinese biotech MagicRNA published data from a Phase I trial of its in vivo mRNA and LNP-based CAR T-cell therapy in five patients with systemic lupus erythematosus. Similar to in Kelonia’s cancer trial, the results were promising. However, larger studies are needed for more conclusive results, as the sample size was small. But rapid, near-complete B cell depletion was seen for up to 10 days with no significant side effects like serious cytokine release syndrome or ICANS.
Since the pandemic, the use of mRNA therapeutics has become much more mainstream. For example, both of the prevalent vaccines against COVID-19 use a combined mRNA–LNP approach. In in vivo CAR T-cell therapy, the LNPs are used to take CAR-encoding mRNA to the right target cells in the body. Once inside a T cell, the LNP breaks apart and releases the mRNA into the cytoplasm. The cell’s protein synthesis machinery reads the mRNA and makes the correct CAR protein, which is then added to the surface of that T cell.
Aera Therapeutics, founded by CRISPR pioneer Feng Zhang, PhD, and based in Cambridge, Massachusetts, takes a combined mRNA–LNP approach to in vivo CAR T-cell therapy development, with a focus on treating B cell-mediated autoimmune disease.
Akin Akinc, PhD CEO, Aera Therapeutics
“We were really focused on autoimmune indications, so we said, ‘Let’s try to build a product profile that’s a great fit for that,’” explained Akin Akinc, PhD, who is CEO at Aera.
“You have the risk of insertional mutagenesis with lentiviral vectors. Even if those rates are small, they’re not zero … So that’s why we thought an mRNA–LNP approach, where there’s no chance of insertion, is theoretically a more attractive approach.”
Aera has not yet moved into clinical studies but reported preclinical data for its therapy candidate AERA-109 in non-human primates at the American Society of Hematology Annual Meeting at the end of last year. They showed potent and durable B cell depletion across different tissues in the body.
One potential disadvantage of using a combined mRNA–LNP approach, particularly for treating cancer, is that it is unlikely to last as long as a lentiviral approach. As this could be potentially advantageous in people with autoimmune disease, where B cell depletion does not need to occur over such a long period of time, it seems to be the most common method followed by companies designing in vivo CAR T-cell therapies for autoimmune conditions.
“Our therapeutic goal is to go in and clear out the B cells that exist in the body, both in the periphery and the tissues, and then allow them to repopulate. If we achieve that immune reset, then that’s all that we can do,” said Akinc.
Scott Barros, Head of Early Development, Akin Akinc, Chief Executive Officer, Bill Querbes, Chief Scientific Officer.
“Then the question is, is there going to be a relapse 12–18 months later? But so long as we clear out all the B cells, which happens pretty quickly, I think there’s no benefit to having the CAR T cells hanging around for longer, because at that point you’ve done the job. Then it’s about whether or not that remission is going to persist.”
NanoCell Therapeutics is also taking a non-viral approach to developing in vivo CAR T-cell therapy for treating B-cell malignancies, but is using DNA instead of RNA. The candidate has not yet reached the clinic, but it has achieved good preclinical results and will soon be tested in non-human primates.
Similar to Aera, NanoCell packages its therapy in targeted LNPs. However, these carry a minicircle DNA that encodes the CAR information and an mRNA transposase that allows the DNA to integrate into the target cell genome.
“We still remain, I think, pretty much in the lead as a company delivering non-viral DNA, because it is very difficult … We see an opportunity for us to actually make a breakthrough there,” said Geerlings.
“The nuclear membrane of the cell is such a barrier. You need to find an opportunity to open it up and to be just in time with your DNA in a way that is not triggering an innate immune response. You also need to have a mechanism by which that DNA can integrate, because otherwise, you will end up having an episomal expression of your DNA.”
The approach taken by NanoCell is definitely at an earlier stage than the lentiviral and mRNA–LNP approaches that are already generating clinical data, but there are a couple of other companies working on similar products, like Stylus Medicine and CPTx. If it works, then this approach has the promise of ruling out problems with viral vectors, such as manufacturing difficulties. It would also theoretically generate longer-lasting and more durable treatment effects than could be achieved with mRNA.
What’s next for CAR T-cell therapy?
It seems that we are on the cusp of next-generation in vivo CAR T-cell therapies, although the studies published so far have all been small and it remains to be seen if the current buzz in the space is based on hype or reality.
“I do think that in vivo will go from a platform with initial proof-of-concept to broad applicability faster than perhaps ex vivo platforms did,” said Hegde. “But we have a lot of scientific questions. For example, in the absence of lymphodepletion, can an in vivo platform give you the depth and durability of response that an ex vivo platform does?”
There is a lot of interest in whether safer and more accessible in vivo CAR T-cell therapy can make this treatment approach more appealing to people with B-cell-mediated autoimmune conditions than autologous CAR T-cell approaches. The initial clinical results are good, but questions remain about how long the results will last.
“I think these are going to work, but we’re going to learn things that allow us to make second-generation products that are even better and even more potent,” said Akinc.
On the cancer side of things, most companies developing in vivo CAR T-cell therapies for oncology indications are sticking with blood cancers against which autologous CAR T-cell therapies have already been shown to be efficacious.
“I think we’ll continue to see strong proof of concept in de-risked indications like the hematologic malignancies over the next year,” said Larson. “Over the next two years, I think we’re going to be closely watching the field for durable outcomes in oncology and the ability to drive immune reset in autoimmune disease that then translates to durable remissions in autoimmune disease patients.”
A big question on everyone’s mind is whether this new technology could help overcome some of the hurdles that prevent CAR T-cell therapy from being successful at treating “solid” tumors, such as working out how to overcome diverse tumor microenvironments.
“I think there’s great potential in solid tumors. One reason why we went with Interius was [that] we think that the application of the in vivo platforms could really break open the problems that we perhaps had in solid tumors with ex vivo CAR T cells,” said Hegde.
“The nice thing about the in vivo space is you can put whatever targeting antigen you want on the virus to go to a specific cell type. So it’s really up to your imagination, how you want to design an in vivo CAR T cell.”
Dispatch Bio is also in the CAR T-cell therapy space, but is targeting solid tumors rather than developing in vivo CAR T cells. The company is based in Philadelphia and was co-founded by Carl June, MD, one of the pioneers of CAR T-cell therapy.
The technology they are developing is a two-component system, in which a human-specific adenovirus designed to infect cancer cells, but not healthy tissue, is used to “paint” the tumor cells so that a CAR T cell can more easily home in on the cancer and destroy it.
Barbra Sasu, PhD Chief Scientific Officer Dispatch Bio
“The virus gets into the tumor microenvironment and then, because it’s a virus, creates an inflammatory condition. When it does that, it’s immediately more supportive for T cells,” explained Dispatch chief scientific officer Barbra Sasu, PhD.
“We’re doing what T cells can’t do for themselves. We’re expressing a target and directing them to kill what we want them to kill. We’re also adding a cytokine to support them and, actually, the endogenous immune system too.”
The two-part approach is very new, so Sasu and colleagues are testing the system using a known autologous CAR T-cell therapy approach. But she says that the system is potentially very flexible and could allow a wide range of therapies, including in vivo CAR T-cell therapies, to be combined with the viral targeting approach if they prove effective.
“What we wanted to do was to start with something that we felt we understood very well. We also had the benefit in our first program of being able to work with people who’ve already developed CAR T-cell therapies,” said Sasu. “That’s a big advantage because [when] coming in with a two-component system, it’s good if you don’t have to refine both parts at once.”
Another CAR T-based approach being developed by Kite and others in this space is logic gating, which is the development of IF, AND, and NOT switches to allow much more refined control of CAR T-cell therapies by clinicians and potentially increase effectiveness in complex solid tumors.
“We’re really interested in exploring the logic gating space and what it can do to deliver CAR T cells more safely, especially in solid tumors, where the antigens aren’t as broadly homogeneously expressed,” said Hegde.
Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. Prior to going freelance, she was editor-in-chief at Labiotech, an English-language, digital publication based in Berlin focusing on the European biotech industry. Before moving to Germany, she worked at a range of different science and health-focused publications in London. She was editor of The Biochemist magazine and blog, but also worked as a senior reporter at Springer Nature’s medwireNews for a number of years, as well as freelancing for various international publications. She has written for New Scientist, Chemistry World, Biodesigned, The BMJ, Forbes, Science Business, Cosmos magazine, and GEN. Helen has academic degrees in genetics and anthropology, and also spent some time early in her career working at the Sanger Institute in Cambridge before deciding to move into journalism.
Neuroblastoma is the most common tumor among children under a year of age, and while in its gentlest form neuroblastoma can regress on its own, it can also take an aggressive form, with high-risk neuroblastoma carrying a five-year survival rate of about 40%.
Researchers at The Hebrew University of Jerusalem have now discovered a mechanistic explanation for how neuroblastoma sustains itself and identified a potential approach to severing that mechanism, by inhibiting nitric oxide (NO) production to suppress mTOR signaling. The collective results from work in human neuroblastoma cells and experiments in a mouse xenograft model showed that inhibiting the enzyme neuronal nitric oxide synthase (nNOS) to inhibit NO production suppressed mTOR signaling and slowed tumor growth.
Professor Haitham Amal, PhD, head of The Laboratory of Neuromics, Cell Signaling, and Translational Medicine, is senior and co-corresponding author of the team’s published paper in Brain Medicine, titled “Targeting nNOS suppresses AKT–TSC–mTOR signaling and inhibits neuroblastoma growth.” In their paper the team concluded “Inhibition of nNOS suppresses mTOR signaling, reduces cellular malignancy, and attenuates tumor growth in vivo, identifying the nNOS-mTOR axis as a promising therapeutic target in neuroblastoma.”
Neuroblastoma accounts for roughly 28% of all cancers diagnosed in infants across Europe and the United States. “Neuroblastoma (NB) refers to a spectrum of neuroblastic tumors that originate from the neural crest cells during fetal development,” the authors wrote. “Neuroblastoma is predominantly a pediatric malignancy, with approximately 97% of cases occurring in children.”
NBs can range from spontaneous regression to maturation to an aggressive, deadly metastatic disease. And as the investigators noted, “Despite major advances in multimodal therapy, high-risk neuroblastoma remains associated with poor prognosis, frequent relapse, and therapy resistance, underscoring the need for a better understanding of the signaling pathways that regulate tumor cell survival, differentiation, and metabolic adaptation.”
Nitric oxide (NO) is an essential regulator of carcinogenesis in various tumors, including NB, the authors pointed out. “Nitric oxide (NO) is a ubiquitous free radical signaling molecule produced in multiple organs and tissues), such as those of the central and peripheral nervous systems.” But at elevated concentrations NO becomes reactive, generating nitrogen species that chemically modify proteins through a process called S-nitrosylation. That modification has been implicated in every stage of cancer progression.
The relationship between nitric oxide and tumors is not simple. Very high concentrations can damage DNA and trigger apoptosis. Lower, sustained levels appear to do the opposite, promoting survival and metastasis. Amal and colleagues had previously demonstrated that nitric oxide drives glioblastoma progression. The question that remained was whether the same enzyme, neuronal nitric oxide synthase, was performing a similar service for neuroblastoma, and if so, through which downstream pathway. The answer turned out to be mTOR.
The team attacked nNOS from two directions. They treated human SH-SY5Y neuroblastoma cells with BA-101, a selective pharmacological inhibitor, at 100 μM for 24 hours. Separately, they silenced the nNOS gene with small interfering RNA. The reasoning was that if a drug and a genetic tool produce the same result, you are looking at biology, not pharmacological noise.
The experiments produced the same result. BA-101 reduced NADPH-diaphorase activity, the standard readout of NOS function, by 35-40%. Genetic silencing cut it by 45-50%. Nitrite levels, a stable proxy for nitric oxide production, fell 65-70% with BA-101 and 55-60% with siRNA. Colony formation, the most direct measure of proliferative capacity, dropped significantly after both BA-101 treatment (p < 0.001) and nNOS silencing (p < 0.01). The cells were losing their ability to multiply.
What followed downstream was systematic. Protein tyrosine nitration, measured by 3-nitrotyrosine immunoreactivity, fell sharply after BA-101 treatment (p < 0.01) and nNOS silencing (p < 0.001). The chemical signature of nitrosative stress was fading.
The results then confirmed that AKT phosphorylation decreased (p < 0.01 with BA-101; p < 0.05 with siRNA), while total AKT remained unchanged. Phosphorylation of mTOR itself declined under both conditions (p < 0.01 each). The downstream mTORC1 substrate ribosomal protein S6 followed (p < 0.05 with BA-101; p < 0.01 with siRNA).
And here, the most telling detail, that TSC2, a master negative regulator of mTOR signaling, rose significantly under both treatments (p < 0.05). Removing the nitric oxide signal had allowed the cell’s own braking system to re-engage. In summary, the authors noted, “Pharmacological inhibition of nNOS with BA-101 (100 μM, 24 h) or genetic silencing of nNOS with siRNA caused upregulation of the key negative regulator TSC2 and decreased phosphorylation of AKT, mTOR, and RPS6, indicating suppression of mTOR pathway activity.”
Synaptophysin, a neuroendocrine tumor marker used to gauge the malignant identity of neuroblastoma cells, decreased significantly with BA-101 (p < 0.01) and nNOS knockdown (p < 0.05). The tumor cells were not merely growing more slowly. They were becoming, at a molecular level, less recognizably cancerous. In summary, the investigators noted, “Our results show that inhibition of NO production in the human NB cell line (SH-SY5Y cells), either by pharmacological intervention using the selective nNOS inhibitor BA-101 (41) or by genetic ablation using the specific siRNA, successfully suppressed NB malignancy.”
Schematic model illustrating the NO-mTOR signaling axis in neuroblastoma. Under basal/pathological conditions (left panel), and nNOS inhibition (right panel). [Haitham Amal]
But if blocking nitric oxide suppresses mTOR signaling, then flooding the cell with nitric oxide should amplify it. The researchers tested this by exposing SH-SY5Y cells to SNAP, a nitric oxide donor, at 200 μM for 24 hours. This converse experiment produced the converse result. 3-nitrotyrosine rose (p < 0.05), and TSC2 fell (p < 0.01). Phosphorylation of AKT, mTOR, and RPS6 all increased (p < 0.05 for each).
The team then tested their findings in a xenograft mouse model of neuroblastoma, treated with BA-101. “Importantly, to extend these findings to an in vivo context, we further assessed the impact of pharmacological nNOS inhibition on tumor growth in a xenograft NB model,” they stated. The investigators found that while tumors in control animals grew to approximately 1.5 cm in their largest dimension, the treated tumors did not. Final tumor volume and weight were dramatically reduced in the BA-101 group. ‘Quantitative analysis revealed a dramatic decrease in the final tumor volume and weight in the BA-101-treated group (p < 0.001) compared with controls,” they noted.
Body weight did not differ significantly between groups, suggesting that the compound was tolerated without gross systemic toxicity. In summary, the authors wrote, “Our finding demonstrate that the pro-tumorigenic effects of nNOS in SH-SY5Y involve activation of themTOR signaling pathway.” Importantly, both genetic inhibition of nNOS using siRNA and pharmacological inhibition with BA-101 effectively suppressed mTOR pathway activation and reduced malignant properties of NB cells, highlighting the therapeutic relevance of targeting nNOS signaling. “These findings indicate that pharmacological inhibition of nNOS effectively suppresses xenograft tumor progression, highlighting the critical role of nNOS-derived NO in promoting neuroblastoma growth in vivo.”
“The magnitude of the in vivo suppression caught our attention,” said Amal, the study’s corresponding author, who holds appointments at the Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, and the Rosamund Stone Zander and Hansjoerg Wyss Translational Neuroscience Center at Boston Children’s Hospital, Harvard Medical School. “We had demonstrated the role of nitric oxide in glioblastoma previously, but the consistency of the neuroblastoma results across every assay, from protein phosphorylation to colony formation to xenograft growth, points to nNOS as something more than a contributor. It appears to be a central driver of the signaling that sustains this tumor.”
Added first author Shashank Kumar Ojha, PhD, first author of the study and a researcher at the Institute for Drug Research, The Hebrew University of Jerusalem, added, “What convinced me was the concordance between the pharmacological and genetic approaches. When BA-101 and siRNA independently produce the same pattern of effects across NADPH-diaphorase activity, nitrosative stress markers, mTOR pathway phosphorylation, and clonogenic growth, you can be confident the biology is real. That reproducibility is what gives you a therapeutic hypothesis worth testing further.”
The authors acknowledged limitations to their study. The in vitro work relied on a single cell line, SH-SY5Y, which cannot capture the full genetic heterogeneity of neuroblastoma or the complexity of the tumor microenvironment. The chemical identity of BA-101 is currently undisclosed pending patent issuance, which means independent replication by other laboratories must wait. Whether nitrosative stress directly underlies its functional impairment, or whether an intermediary mechanism is involved, remains an open question that the authors explicitly flag for future investigation. “Future studies using patient-derived cells, organoids, or genetically engineered mouse models will be important to further validate and extend these observations,” they stated. Nevertheless, the authors suggest, the limitations do not diminish the central discovery of a druggable nNOS–mTOR axis.
mTOR inhibitors such as rapalogs and catalytic mTOR inhibitors have shown limited efficacy as monotherapies in neuroblastoma, undermined by feedback activation and resistance mechanisms. The present study suggests the potential for a different attack strategy. Rather than targeting mTOR at the lock, intervene upstream at the hand that turns the key. By reducing nitric oxide-dependent mTOR activation, nNOS inhibition may sidestep the compensatory pathways that have frustrated direct mTOR blockade. “Collectively, these results identify the nNOS-mTOR axis as a key driver of neuroblastoma progression and suggest that nNOS inhibition represents a promising strategy for NB treatment,” they concluded.
Researchers at NYU Abu Dhabi have developed manganese-based molecules that combine cancer detection and treatment within a single system, allowing for simultaneous imaging and therapy using magnetic resonance imaging (MRI). The research, published in the Journal of the American Chemical Society, details the development of metal–organic structures that remain stable in healthy tissue but become active within the tumor microenvironment, where they both enhance MRI contrast and induce cancer cell death.
“Our goal was to create materials that allow doctors to see cancer clearly and treat it at the same time,” said lead author Farah Benyettou, PhD, a research scientist at NYU Abu Dhabi. “The ability to image and target brain tumors with high precision is particularly exciting.”
The molecules the researchers developed are composed of manganese ions coordinated with organic frameworks arranged into interlocked topologies. Unlike conventional drugs, which are small and relatively simple, these molecules have interlocked structures that resemble knots and rings. This design allows them to behave differently inside the body, improving both imaging and therapeutic performance.
“Manganese (Mn)-based metal–organic architectures offer a unique avenue for integrating magnetic resonance imaging (MRI) and cancer therapy within a single molecular platform,” the researchers wrote. The geometrical complexity and electropositive, pH-labile coordination framework allow the molecules to remain intact in normal tissue but disassemble when exposed to the acidic tumor microenvironment.
This pH-responsive behavior is the key to their dual function. In healthy tissue, the molecules maintain stability and limit off-target effects. Once inside tumors, where acidity is elevated, they release Mn2+ ions. These ions enhance T1-weighted MRI signals, making tumors more visible, while also triggering biological pathways that lead to cancer cell death. The researchers wrote that this process culminates in “lysosomal acidification, pH-triggered disassembly, Mn2+ release, ROS accumulation, and caspase-dependent apoptosis,” marrying their imaging capability directly to therapeutic action.
The novel molecule design builds on prior prior research of manganese-based imaging agents and topological chemistry. The researchers noted that conventional gadolinium-based contrast agents have safety limitations, including toxicity and accumulation in tissues, while earlier manganese agents lacked stability and tumor targeting. “These drawbacks underscore the need for next-generation Mn platforms with enhanced stability and tumor specificity,” the researchers wrote. In previous studies, the NYU Abu Dhabi researchers had demonstrated that metal-templated trefoil knots could induce apoptosis in drug-resistant cancer cells, a finding that spurred their efforts to integrate therapeutic activity with an imaging agent.
To evaluate the new molecules, the team conducted both in vitro and in vivo experiments, focused on glioblastoma. In cell studies, Mn-TK and Mn-BR showed selective toxicity toward cancer cells while sparing normal cells. In animal models, the molecules accumulated in tumors, produced strong MRI contrast, and inhibited tumor growth.
An important finding of the study was data that showed both Mn-TK and Mn-BR were able to cross the blood–brain barrier and accumulate in glioblastoma tumors. This has traditionally been a major limitation of MRI contrast agents, which often fail to image tumors in the brain.
The implications for clinical care include the potential to replace separate diagnostic and therapeutic steps with a single intervention. By combining imaging and treatment, the molecules could provide earlier detection, more accurate tumor delineation, and targeted therapy with reduced side effects. The manganese-based design may also offer a safer alternative to gadolinium, which could produce long-term retention and toxicity.
“This work introduces a generalizable strategy for designing manganese-based theranostic agents by integrating topological coordination chemistry with tunable lipophilicity and electrostatics,” the researchers noted, adding that this method could be used to develop additional agents tailored to different cancers or imaging needs.
Next steps for the team include further evaluation of safety, optimization of molecular design, and studies to support clinical translation. The researchers identify Mn-TK and Mn-BR as leading candidates due to their combination of tumor targeting, imaging performance, and therapeutic activity. Continued work will likely focus on refining these properties and assessing their performance in additional disease models.
A “smart contact lens” can monitor eye pressure and manage and release glaucoma drugs to counteract any rises in this, preclinical research suggests.
The all-polymer, microfluidic lens, described in Science Translational Medicine, represents further progress towards personalized eye technologies in a “theranostic” approach that combines diagnostics and therapy.
The battery-free device was able to monitor intraocular pressure—the most prominent, modifiable risk factor for glaucoma—and could release glaucoma drugs timolol and brimonidine at pressure thresholds in animal studies.
The device could one day provide frequent, real-time pressure monitoring with responsive drug release for patients at home, offering an alternative to the infrequent gold-standard measurements in the office, which only occur every six to 12 months.
“This electronic- and power-free device combines softness, optical transparency, biocompatibility, and cost-effectiveness, offering a noninvasive approach to continuously monitor IOP and deliver individualized therapy,” reported Yuting Cai, PhD, from Hong Kong University of Science and Technology, and co-workers.
They added: “Beyond glaucoma, the platform is compatible with commercial soft contact lenses and can be reconfigured to monitor additional tear biomarkers, enabling a wider range of ocular care applications.”
Biosafety assessment of AP-TSCL-Timo and AP-TSCL-Pro after two weeks of wear [Yangzhi Zhu, Terasaki Institute for Biomedical Innovation]
Glaucoma is often referred to as the “silent thief of sight” and is the leading cause of irreversible blindness worldwide.
Its prevalence is predicted to increase sharply due to aging populations, rising from 80 million people in 2020 to around 134 million in 2040.
Although it is progressive and incurable, early diagnosis and treatment can preserve vision and maintain quality of life, although this requires reliable tools to identify those at risk and deliver therapies.
While smart contact lenses represent a promising platform to deliver this, the need to embed electronics, power sources, and manufacturing costs represent potential barriers in terms of patient comfort and accessibility.
To address this, the team developed an all-polymer theranostic smart contact lens (AP-TSCL) capable of continuously measuring intraocular pressure with autonomous programmable drug delivery without the need for bulky electronic components or manual operation.
The lens integrates a noninvasive, real-time microfluidic sensor that measures intraocular pressure together with a multidose, feedback-responsive drug release unit.
A biomimetic silk sponge enhances both its sensing sensitivity and the consistency of drug delivery, providing high mechanical robustness and operates well over a physiological pressure range of 16 to 32 mmHg.
By coupling the intraocular pressure readout with pressure-gated drug release, the platform is designed to enhance therapeutic efficacy while reducing unnecessary exposure under normotensive conditions. This may help mitigate ocular irritation and systemic side effects associated with conventional topical β-blockers in susceptible patients, the authors explain.
Comprehensive in vitro, ex vivo studies in cow eyes, and in vivo studies in rabbits validated its biocompatibility, accuracy, and therapeutic efficacy, demonstrating its potential as a low-cost, patient-compliant platform for personalized glaucoma therapy in real-world settings.
“This power- and electronic-free SCL represents a remarkable advancement toward multifunctional ocular medical devices that integrate diagnostics and therapeutics for intelligent ocular health care delivery,” the research team maintained.
“It lays the groundwork for developing a family of pharmacy-on-a-contact-lens tools capable of delivering clinically relevant information about human health and establishes the foundation for next-generation, self-powered, electronic-free SCLs capable of accessible diagnosis and therapeutics.”
Stanford researchers have developed a urine test that can accurately predict which patients with bladder cancer will respond to standard surgery and immunotherapy treatments. In a study published in Cell, they report that this DNA test takes into account background mutations caused by aging that existing tests may otherwise mistake for cancer.
“Our test can detect minimal residual disease non-invasively after bladder cancer treatment, while accounting for mutations present in normal urothelium that have complicated prior studies,” said Joseph C. Liao, MD, professor of urology and senior author of the study. “For the first time, we were able to distinguish patients likely cured by [immunotherapy] from those cured by surgery.”
Even when detected in early stages, bladder cancer has a high relapse rate. Patients with non-muscle invasive bladder cancer (NMIBC), whose tumors are still confined to the inner layers of the bladder, are typically treated with surgery. Those with higher risk profiles are then given a bacillus Calmette Guerin (BCG) immunotherapy, which can significantly reduce recurrence risk after surgery.
However, while some patients respond well to surgery without immunotherapy, others may end up relapsing even after receiving BCG immunotherapy. Until now, there was no reliable way to predict which patients will respond to each of these treatments, making it difficult for physicians and patients alike to make informed clinical decisions.
The molecular test developed by Liao and colleagues analyzes urine tumor DNA in urine samples to detect the presence of tumor DNA and predict whether a patient will respond to standard surgery or BCG treatment. Importantly, the test was designed to account for the “field effect,” a phenomenon where even healthy people can carry cancer-associated mutations in the bladder’s lining, with these mutations becoming increasingly common as the person ages.
“By correcting for the field effect, a known confounder of mutation-based bladder cancer detection, we improved the specificity of urine tumor DNA liquid biopsies,” said William Y. Shi, MD/PhD student at Stanford School of Medicine and lead author of the study. “This allowed us to molecularly distinguish the relative contributions of surgery and BCG to disease control.”
The researchers evaluated the urine test in a cohort of 261 NMIBC patients who underwent surgery and BCG treatment. Results revealed three distinct molecular patterns of treatment response. These included surgery responders, for whom tumor DNA disappeared after surgery; BCG responders, who showed tumor DNA after surgery that was eliminated with the immunotherapy; and non-responders who saw tumor DNA levels remain stable or even increase after both treatments.
“The ability to distinguish responders from non-responders to the two treatments also allowed us to study which molecular properties make tumors more likely to benefit from each therapy,” said Max Diehn, MD, PhD, professor of radiation oncology and senior author of the study.
The study also revealed distinct molecular patterns driving response to surgery and response to BCG immunotherapy. On the one hand, patients who relapsed after surgery had tumors with genetic activity linked to cell growth and invasion. On the other hand, tumors who responded to BCG had a higher mutation burden and tended to have features that made them more visible to the immune system.
Following validation in a larger patient cohort, this urine test could help spare patients who respond well to surgery from receiving an unnecessary course of immunotherapy. In particular, BCG supply has suffered from shortages for the past decade, leaving many patients waiting for longer than necessary. In the face of shortages, a predictive test could help prioritize those who are most likely to benefit from it.
For patients who are unlikely to respond to both surgery and BCG, the urine test could also prove valuable in escalating treatment early on. In the study, the test was able to identify recurrence risk in patients for whom routine cystoscopy exams appeared normal, meaning it could be able to detect relapse earlier than the current standard.
“These kinds of predictive biomarkers are critical,” said Eila C. Skinner, MD, professor of urology and chair of Stanford’s Department of Urology. “We have new treatments that are costly and carry risk of side effects. We would love to personalize therapy to ensure each patient receives the best treatment for their individual cancer.”
Researchers from Ohio State University have developed a gene therapy that promotes blood vessel growth following nerve graft surgery. A study published today in Science Advances reports a significant improvement in both nerve growth and muscle strength in treated mice.
Peripheral nerve injury can cause long-term disability, weakness, numbness, or loss of function. While nerve grafts can help repair some of these injuries by regrowing damaged nerves and reconnecting any gaps left by the original injury, many patients still can’t fully recover mobility or feeling.
The new approach developed at Ohio State combines traditional nerve graft surgery with a gene therapy delivered using quick electrical pulses to the nerve drafts. This technique, known as tissue nanotransfection (TNT) is used to introduce three genes (Etv2, Fli1 and Foxc2) into graft cells that promote the formation of new blood vessels.
“This study is the first to combine TNT with nerve graft surgery,” said Daniel Gallego-Perez, PhD, professor of biomedical engineering at Ohio State and senior author of the study. “While healing nerves do need oxygen and nutrients, blood vessels do much more than just deliver supplies—they help guide and support the repair process. By helping the body quickly grow new blood vessels, our approach creates a healthier environment that allows nerves to heal more effectively.”
In a mouse model of peripheral nerve injury, mice treated with the gene therapy grew more blood vessels than those only receiving a conventional nerve graft surgery. The treatment did not just help nerves regrow and reconnect, but also improved function and general health outcomes in mice.
“We saw improvements not just under the microscope, but in real function like stronger muscle contractions and better grip strength,” said Amy Moore, MD, chair of Ohio State’s Department of Plastic and Reconstructive Surgery and interim dean of the university’s College of Medicine. “The findings from this study advance our ability to reconstruct long nerve gaps and restore function to limbs with devastating nerve injuries.”
Moore noted that this approach could make a significant difference when treating severe, complex nerve injuries common among military services injured in training or combat. The treatment is being developed as part of the Military Medicine Program at Ohio State, which focuses on offering surgical reconstruction and pain management care for wounded service members.
Development of the gene therapy will continue with studies in larger animals before human trials can begin. Next, the research team plans to investigate how long the benefits of the treatment last.
This novel approach could one day become part of routine nerve graft surgery, adding a simple short step to significantly improve the outcomes of a well-established procedure. Salazar-Puerta added: “This is designed to fit into the operating room and is a single treatment that could have lasting benefits.”
On any given morning, skyrocketing numbers of people reach for a small injection pen (and soon a pill) that, just a few years ago, was barely available outside of diabetes clinics. Drugs like semaglutide and tirzepatide have become cultural phenomena, reshaping not only medicine but also public discourse and the advertising industry around weight, metabolism, and obesity. Today, it is impossible to open a magazine, turn on the TV or radio, or walk down the grocery aisle without encountering some form of advertisement for these GLP-1 receptor agonists (GLP-1RAs).
Almost any individual in the United States can obtain a subscription to a GLP-1RA without having to visit a doctor’s office. Just visit Hims/Hers, Ro, or Noom and answer a few questions about weight, height, goals, and concerns to get a prescription. (One such site claims it is taking weight and height data and “combining with clinical data,” whatever that means, before presenting a plan and steps for ordering a prescription.)
But there are some major problems, one being that these drugs don’t work uniformly. Some patients respond to GLP-1RAs almost immediately, reporting diminished cravings within days. Others see little change. Side effects, too, can vary dramatically, from mild discomfort to debilitating nausea and vomiting. The spread of outcomes is wide and not fully understood.
Before blindly beginning to take a drug that, on the one hand, has seemingly miraculous effects and, on the other hand, might cause serious side effects like pancreatitis, gallbladder disease, and kidney failure, wouldn’t prescribers and prescription seekers want to know this information?
A study published in Nature by the 23andMe Research Institute—the new nonprofit entity founded by the company’s co-founder, Anne Wojcicki, for $305 million to replace the bankrupt biotechnology company—suggests the answer may be found, at least in part, in something far more fundamental than diet or willpower: our genes.
In speaking with Inside Precision Medicine for the first time since the company filed for bankruptcy and was resold to the nonprofit public benefit corporation, Adam Auton, PhD, vice president of Human Genetics at the 23andMe Research Institute, said, “The ‘GLP-1s’ have completely transformed weight loss management. A huge fraction of the population is benefiting. It’s a very natural question: Are people’s experiences on GLP-1s modulated by genetics?”
The short answer is, yes. Auton and 23andMe Research Institute scientists have provided genetic evidence that variation in drug target genes contributes to variability in response among individuals, laying the groundwork for consumer-based precision medicine approaches to obesity treatment and beyond.
Crowd-sourcing GLP-1 genetics
To better understand why responses to GLP-1 receptor agonists vary so widely, the 23andMe Research Institute team leveraged its uniquely large and engaged research cohort. Over the past decade, the company has assembled genetic data from more than 15 million participants who consented to research, enabling analyses that would be difficult in traditional clinical trials. Immediately following the company’s filing for bankruptcy in March 2025, 23andMe reported that over 1.9 million users requested for their data to be deleted. Auton told Inside Precision Medicine that the current number of consented customers is around 11 million.
Building on this resource, Auton and colleagues launched a targeted survey asking participants detailed questions about their GLP-1 drug use, including medication type, duration, dosage, weight loss, and side effects. More than 27,885 customers responded, providing a rich, real-world dataset. “That’s the power of having a large, engaged cohort,” said Auton. “You can ask a question and very rapidly get meaningful data back.”
Using these data, Auton and colleagues conducted a genome-wide association study (GWAS), scanning millions of genetic variants to identify those associated with treatment outcomes. “You’re starting with the entire genome,” Auton explained. “You’re testing every variant for correlation with the trait of interest. And when you see a signal, it tends to be overwhelming.”
The team focused on two primary traits: weight loss and the presence of side effects. The strongest association emerged in GLP1R, the gene encoding the GLP-1 receptor—the direct target of these drugs. A missense variant, rs10305420, was linked to significantly greater weight loss, with each copy associated with an additional 0.76 kilograms lost.
“It made very clear biological sense,” Auton said. “This is the receptor that the drug is acting on.” The missense variant may affect how much receptor is expressed on the cell surface, meaning individuals with more receptors could experience a stronger response to the same dose.
A second key finding involved a substitution in GIPR (rs1800437; p.Glu354Gln), which encodes the receptor for glucose-dependent insulinotropic polypeptide and is targeted by dual agonists such as tirzepatide. Unlike the GLP1R result, this association was not related to weight loss but to drug tolerability. Carriers of the variant were more likely to report nausea and vomiting—but only when taking medications that act on the GIP receptor. No such effect was observed among users of semaglutide, which does not target GIPR.
“It was very, very clean,” Auton said. “We saw this effect specifically in people taking the medications that actually target that receptor.”
Together, these findings underscore a central principle of pharmacogenetics: genetic variation can shape not only whether a drug works, but also how it is experienced, often in highly drug-specific ways.
Who is represented
One of the study’s more unconventional aspects is its reliance on self-reported data, a method sometimes viewed with skepticism in clinical research given the limits of memory and potential inaccuracies in reporting weight loss or medication use. Anticipating this concern, scientists at the 23andMe Research Institute validated their findings using a subset of participants who also shared electronic health records (EHRs), enabling direct comparison between self-reported and clinically recorded data.
The results were reassuring: survey-reported weight loss closely tracked with medical records, and medication histories aligned well across both sources. Although participants tended to slightly overestimate weight loss, they also reported longer treatment durations, effects that largely offset each other. Importantly, the genetic associations remained robust under independent scrutiny, with replication in the All of Us Research Program, a large, federally funded dataset based on clinical records rather than self-report.
While weight loss is the headline feature of GLP-1RAs, side effects often determine whether patients persist with treatment. Nausea, vomiting, and gastrointestinal discomfort are among the most common reasons for discontinuation, yet they are frequently underreported in traditional clinical datasets. EHRs may document when a medication is stopped but rarely capture why. Self-reported data addresses this gap by directly capturing patient experience.
“We were able to ask people directly about their experiences,” Auton said. “That’s something that’s often missing from clinical datasets.” By linking these experiences to genetic variation, the study enables a more refined understanding of drug tolerability, moving beyond population averages to individualized risk profiles.
As with many large-scale genetic studies, statistical power was greatest among individuals of European ancestry, reflecting broader imbalances in genomic datasets. However, the key findings were consistent across multiple ancestral groups, supporting their generalizability.
“We’re not seeing fundamentally different genetic effects across populations,” Auton said. Still, increasing diversity in genetic research remains essential to ensure equitable advances in precision medicine. As digital tools continue to integrate genetic, clinical, and self-reported data, this participant-driven model may play an increasingly central role in biomedical discovery.
Putting pharmacogenomics in patients’ hands
Identifying genetic variants is only the first step, of course. The larger goal is to translate those discoveries into tools that can guide real-world decisions. To that end, the 23andMe Research Institute scientists developed predictive models that combine genetic information with clinical factors to estimate treatment outcomes.
The vision is straightforward: before starting a GLP-1 drug, a patient could receive a personalized profile indicating likely weight loss and risk of side effects. “People are making decisions about whether these medications are right for them,” Auton said. “Can we give them information to help with that decision?”
Such tools could have immediate clinical applications. A patient with a high predicted risk of nausea, for example, might start at a lower dose or follow a slower titration schedule. Another with a favorable genetic profile might be reassured about expected benefits.
For now, these findings are unlikely to immediately change prescribing practices, as clinical guidelines will require further validation through prospective studies. However, the trajectory is clear. In the near future, patients considering GLP-1 therapies may undergo genetic testing as part of routine care, with treatment decisions—such as drug choice, dosing, and expectations—guided in part by their DNA. For a class of drugs already transforming millions of lives, this approach could further enhance both efficacy and tolerability, underscoring that responses to GLP-1 therapies are shaped not only by pharmacology but also by the subtle variations of the human genome.
The broader significance of the study lies in its contribution to precision medicine: the idea that treatments should be tailored to individual biology rather than applied uniformly. In fields like oncology, this approach is already standard. But precision obesity treatment is in far earlier stages.
Auton is quick to re-emphasize that genetics is only one piece of the puzzle. Lifestyle, environment, treatment adherence, and underlying health conditions all shape outcomes. Still, even a partial predictive signal could be transformative in a field where trial-and-error prescribing is common.
As researchers continue to study GLP-1RAs, their potential appears to extend far beyond weight and blood sugar. Early evidence suggests benefits in cardiovascular health, inflammation, and even neurological conditions. Some studies are exploring their role in addiction and compulsive behaviors. “There’s an increasing literature that they’re beneficial in multiple areas,” Auton said.
This expanding scope makes understanding variability even more important. If GLP-1 drugs are to be used to treat a wide range of conditions, predicting who will benefit and who may be at risk becomes one of the most important, if not the most important, challenges.
What about sequencing?
Throughout our conversation, there was at least one elephant in the room. One is that this is not the first study to identify genetic variants influencing responses to GLP-1 drugs, as prior research has also implicated rs10305420. Slovenian researchers showed that genetic variability in GLP1R is associated with inter-individual differences in the weight-lowering-lowering potential of GLP-1 drugs in obese women with polycystic ovary syndrome (PCOS) in 2015, at a time when the main GLP-1 drug was liraglutide, which required daily injection.
More provocative is that the directionality of the variants’ effect reported in the Nature paper is the opposite of these previous studies. Auton’s team writes that such discrepancies may stem from differences in disease context, smaller sample sizes, limited statistical power, and variations in drug type, cohorts, and analytical methods.
Additionally, the GIPR variant rs1800437 (p.Glu354Gln) is already a known partial loss-of-function mutation, previously identified in a study of Chinese type 2 diabetes patients in 2019.
Perhaps the more significant issue is the question of sequencing. It’s not a space that 23andMe has completely avoided, as their premier consumer kit employs exome sequencing. But the cost of whole genome sequencing (WGS) direct-to-consumer products is now often priced lower than 23andMe’s premier kit, which goes for $499.
When asked about employing WGS, Auton revealed little of the calculus behind why 23andMe hasn’t added WGS to its arsenal of tools for interrogating genomes. “We’re very excited about that space,” Auton said. “Our focus has always been on what we can do in a direct consumer framework. There’s always been a price question there for WGS. It’s great. But when it was $1,000, it wasn’t obvious that that was going to be a compelling consumer offering. The pricing has reached its current level. It’s an area we’re very excited about and we’ll continue to look at.”
With studies like this, 23andMe 2.0 is making a case, perhaps its strongest yet, that its true value lies in something far more consequential: the ability to predict how individuals will respond to medicine before they ever take it. If that vision holds, the implications extend well beyond GLP-1 drugs. It suggests a future where prescribing a medication without first consulting a patient’s genetic profile feels incomplete, even irresponsible.
Glaucoma is the second-leading cause of blindness, and a silent one at that. It’s estimated that half of the patients who develop it are unaware of their condition, as they lose peripheral vision only when the disease is more advanced, and the damage is irreversible.
There isn’t a cure, and while medication can control hypertension in the eye to slow or stop further damage to the optical nerve, it has shortcomings.
The ability to update actions depends on the thalamus’s parafascicular nucleus (PF); however, which PF’s inputs control this function is unknown. Here, using fiber photometry, retrograde labeling, ex vivo electrophysiology, and optogenetic manipulations, we identify the contribution of the PF and its glutamatergic inputs to the update from a spatial to a visually guided strategy in a set-shifting task conducted in mice (of either sex). Our results show the following: (1) GCaMP signals from the PF recorded along the update from a spatial to a visual strategy correlate with the probability of selecting the correct action based on a light stimulus. (2) Optogenetic inhibition of the PF during this update decreases the probability of selecting the correct action. (3) The mesencephalic locomotor region (MLR) was found to have the highest probability of synaptic connections with the PF. (4) GCaMP recordings from the MLR->PF input support it as a main driver in allowing the PF update function. (5) Inhibition of the MLR->PF connection decreases the probability of updating the contingency. These findings identify the inputs from the MLR as a crucial driver of the PF’s role in controlling the update of actions.
![Schematic model illustrating the NO-mTOR signaling axis in neuroblastoma. Under basal/pathological conditions (left panel), and nNOS inhibition (right panel). [Haitham Amal]](https://www.genengnews.com/wp-content/uploads/2026/04/Low-Res_Amal-Figure1-2026-Screenshot-2026-04-01-at-11.41.51-300x153.jpg)
