Perioperative neurocognitive disorders, an umbrella term encompassing preoperative cognitive impairment, acute postoperative delirium, and longer term postoperative neurocognitive disorders, represent significant complications for the growing population of older surgical patients. The rising prevalence of metabolic syndrome, defined by the clustering of abdominal obesity, insulin resistance, hypertension, and dyslipidemia, necessitates a deeper understanding of its impact on the perioperative brain. This comprehensive review elucidates the intricate epidemiological and mechanistic links between metabolic syndrome and the spectrum of cognitive decline. Epidemiologically, we disaggregate the risk profiles of individual components, demonstrating that distinct metabolic phenotypes serve as specific predictors for different phases of impairment. Mechanistically, we propose a sequential pathophysiological cascade where chronic systemic inflammation primes the brain for injury. Surgical stress triggers the failure of a compromised blood brain barrier, leading to the activation of the TLR4/NLRP3 inflammasome and the induction of central insulin resistance. These processes ultimately culminate in mitochondrial energy crises and synaptic degradation. To address these vulnerabilities, we evaluate an integrated perioperative strategy spanning preoperative metabolic optimization, intraoperative management, and emerging pharmacological interventions such as SGLT2 inhibitors and mitochondria targeted antioxidants. Critically, this review identifies a major knowledge gap regarding the absence of dedicated randomized controlled trials targeting the surgical metabolic syndrome population. Ultimately, our findings advocate for a clinical paradigm shift toward phenotype specific metabolic optimization to improve neurocognitive outcomes in these high risk patients.
Food-i-Sense Analytics: Integrating AI Into Continuous Glucose Monitoring Data Analysis for Precision Nutrition.
Conditions: Prediabetes (Insulin Resistance, Impaired Glucose Tolerance); Artificial Intelligence Mobile Application
Interventions: Device: Continuous glucose monitoring using a wearable sensor (flash interstitial glucose monitor)
Sponsors: IMDEA Food; Abbott Laboratories (Pak) Ltd.
Not yet recruiting
Interventions: Device: Continuous glucose monitoring using a wearable sensor (flash interstitial glucose monitor)
Sponsors: IMDEA Food; Abbott Laboratories (Pak) Ltd.
Not yet recruiting
Engineered Islets Could Eliminate Need for Immunosuppression in Type 1 Diabetes
Researchers at the University of Missouri School of Medicine have developed a method to transplant insulin-producing islets for type 1 diabetes (T1D) treatment that illuminate the need for immunosuppressive drugs. The approach, details of which are published in JCI Insight, uses ex vivo engineering of donor islets with immune-regulating molecules that reduce both innate and adaptive immune rejection after transplantation. By adding thrombomodulin (TM) and CD47 to the surface of islets, the team created a localized immune-modulating barrier that allowed transplanted cells to survive and function while still responding to glucose and producing insulin.
“Immunosuppressant medications affect and weaken the whole body, so we instead focused on how we could improve our delivery of the transplanted islets,” said study senior author Haval Shirwan, PhD, a professor of molecular microbiology and immunology at University of Missouri. “We provided islets with a protective shield consisting of two molecules that help the transplants evade rejection from the immune system, a solution that lengthens the survival of islet cells with minimal side effects.”
To create the islets, the researchers used a surface-engineering approach known as a ProtEx platform. Islets were biotinylated and then coated with streptavidin-fused immune ligands (SA-TM and SA-CD47), allowing transient display of immune-regulating proteins without genetic modification. The purpose of this design was to reduce early inflammatory injury and block immune cell activation signals that normally lead to graft destruction following transplantation.
To discover whether these engineered cells reduced immune response, the cells were testing in allogenic mouse models. The data showed that in eight of the 11 mice tested the grafts survived from 120 to 330 days without resulting immunosuppression. By comparison unmodified islets were rejected quickly in the mouse models with survival time averaging 12 days.
The team also showed that islets engineered with only one of the molecules had limited benefit, while islets with both TM and CD47 produced the strongest effect. In recipients receiving modified islets, normal blood glucose levels were achieved in more than 72% of the mice, and the grafts maintained glucose-responsive insulin secretion.
The inclusion of two different molecules on the islets served different purposes. TM was used to reduce early inflammatory and coagulation-driven damage that occurs immediately after transplantation, while CD47 signaled to immune cells to inhibit phagocytosis and dampen adaptive immune activation.
“The double-engineered islets generated a localized tolerogenic immune environment characterized by low frequencies of inflammatory innate immune cells and increased frequencies of M2 macrophages, myeloid-derived suppressor cells, and CD4+FoxP3+ T regulatory cells,” the researchers wrote.
This new approach builds on the team’s prior work which showed that single-molecule engineering of islets with either CD47 or TM could partially improve graft survival. Earlier studies demonstrated that CD47 signaling reduced immune cell–mediated killing and that TM reduced early inflammatory injury linked to coagulation and cytokine release.
Importantly, the researchers noted that the engineering process does not impair islet function, viability, or metabolic activity, which can frequently happen as a result of cell engineering. Because the proteins are displayed transiently on the islet surface rather than permanently encoded, the methods does not produce long-term genetic alteration but still reshapes early immune responses during transplantation.
The researchers said that additional work now needs to evaluate the safety and effectiveness of these cells in humans and to determine whether the approach can reduce or eliminate the need for multiple donor islet sources, which are needed in current approaches due to early immune loss. The study also suggests that the modular nature of the platform could allow additional immune-regulating molecules to be added to further improve outcomes or tailor responses in different patients.
The post Engineered Islets Could Eliminate Need for Immunosuppression in Type 1 Diabetes appeared first on Inside Precision Medicine.
Feasibility of Technology-Assisted Lifestyle Self-Monitoring in Older Adults With Type 2 Diabetes: Mixed Methods Pilot Study
Background: Type 2 diabetes is a major public health concern in older adults. Healthy lifestyles, such as physical activity and healthy eating, are effective strategies for diabetes self-management. Increasing evidence shows that health technologies can promote healthy lifestyles for diabetes management. However, limited research has evaluated their use among older adults with type 2 diabetes. Objective: This study evaluated the feasibility and preliminary health outcomes of technology-assisted lifestyle monitoring for diabetes management in older adults with type 2 diabetes. The study also examined participants’ experiences to identify barriers and facilitators to sustained technology-assisted lifestyle modification. Methods: This 12-week pilot study used a pretest and posttest design. Feasibility was assessed by recruitment, retention, and adherence to device-based self-monitoring, including the percentage of days with tracked steps (PDWTs) and the percentage of days with food logs (PDWFLs). Fitbit fitness trackers paired with smartphone apps were used to track physical activity and food intake in 15 overweight/obese older adults with type 2 diabetes (mean age 70.5, SD 4.8 y). Self-monitoring behaviors were tracked throughout the study. Baseline and 12-week health outcomes (eg, hemoglobin A [HbA] and physical function) were compared using paired 2-tailed tests or Wilcoxon signed rank tests, as appropriate; effect sizes were calculated using Cohen . Associations between self-monitoring data (PDWTs, average daily steps, PDWFL) and health outcomes were examined using Pearson or Spearman correlations. Semistructured interviews were conducted at the study completion, and thematic analysis was used to analyze qualitative data. Results: The target sample (n=15) was successfully enrolled over 6 months, with 100% retention at 12 weeks. Feasibility was supported by consistent use of wearable devices for self-monitoring of physical activity, although dietary logging adherence varied. HbA decreased from baseline to 12 weeks (effect size −0.49, 95% CI –1.15 to –0.04; =.04), and PDWFL was inversely correlated with HbA (=−0.53; =.04) at follow-up. The qualitative findings indicated that barriers and facilitators to technology-assisted lifestyle self-monitoring and diabetes management through lifestyle modifications exist across multiple levels, including the individual, interpersonal, organizational or community, and societal levels in older adults with type 2 diabetes. Factors at one level interacted with those at other levels. For example, limited technological proficiency challenged lifestyle tracking, while interpersonal and organizational support helped mitigate barriers. Conclusions: Technology-assisted self-monitoring of lifestyle behaviors was feasible in this sample of older adults with type 2 diabetes and was associated with favorable signals in glycemic control. While causal inferences cannot be drawn from this single-arm pilot study, observed within-subject changes and behavioral-clinical correlations support further evaluation of technology-assisted lifestyle self-monitoring. The findings also highlight the importance of addressing interconnected factors at multiple levels, tailored to older adults’ unique needs and capacities in diabetes self-management.
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Arthur Caplan: The Right to Life, Liberty, and Pursuit of Health
Arthur Caplan’s reflections on medical ethics draw not only on theory but also on lived experience. As a child hospitalized during the polio era, he watched doctors shield families from harsh truths, promising sick children would “go home” when they clearly would not. That early encounter with paternalism sparked a career questioning who medicine serves, who gets protected, and who gets left behind.
In this episode of Behind the Breakthroughs, Caplan argues that modern bioethics is undergoing a profound transformation. Medicine once viewed disability almost exclusively as a problem to “fix,” often with horrifying consequences. He recalls a time when infants born with conditions like Down syndrome or spina bifida were denied treatment and allowed to die. Today, he warns, the danger is subtler but equally troubling: a culture of genetic testing and parental perfectionism that risks defining human worth by what technology can detect.
Caplan also sees a seismic ethical shift from protection to autonomy. Research ethics once focused on shielding vulnerable people from dangerous experimentation after scandals like Tuskegee and the Willowbrook State School. Now, fueled by post-COVID distrust and libertarian politics, public pressure favors “right to try” medicine and personal choice even when evidence is weak or risks are high.
Yet Caplan draws a sharp line at public health. Vaccines, he argues, are not merely personal decisions but moral obligations rooted in responsibility to others. He warns that an obsession with liberty, detached from community ethics, threatens the foundations of public health itself.
Caplan also looks ahead, discussing what he thinks will define the next ethical frontier, the brain. If we can alter the brain, how much can we change and still remain ourselves?
This interview has been edited for length and clarity.
IPM: How did you become interested in medical ethics?
Caplan: When I was about six, in 1956, I was playing with my parents in their bedroom, rustling around, when they noticed my legs weren’t moving well, and my mother freaked out because she knew that meant maybe polio. It was something that all parents knew about at that time, fearing it was incurable, sometimes fatal, and often disabling.
You didn’t know even what to do to prevent it. People tried to close down swimming pools and not have summer camp, but it wasn’t clear what the route of transmission was. They didn’t understand that it could be in wastewater or fecal material.
Off I went, living in Boston, to Mass General. The experience definitely shaped me in many ways in terms of outlook and career. At the time I didn’t like the fact that the doctors and nurses didn’t tell us the truth. They often said, “Arthur is going to go home,” and Arthur was clearly pretty sick, and he didn’t go home. That’s a long-winded way of explaining the genesis of my interest in medical ethics.
One other thing that was interesting that people forget when a newborn is born with a birth defect when they go into a sort of neonatal peds rotation is if the parents say there’s a birth defect and we don’t want it treated, the doctors do not. That included spina bifida. In fact, it included Down syndrome. Those infants were put in a corner and allowed to die through starvation.
IPM: How is genetic testing changing society’s perception of what constitutes an “acceptable” human being, as well as medicine’s responsibility to treat all humans?
Caplan: The idea that medicine has always had a view that disability is something that you have to treat—I don’t agree with that totally. I would like to see that treated as an open question, not a close one. It’s also clear that aside from medicine’s views of disability, the line shifts technologically; some of the things that are disabling are less so as we get better technology.
At NYU, we do face transplants…but we, interestingly, have not really gotten into limb and hand transplants. The reason is we think that the prosthetic opportunities are so good that there’s no reason to do a procedure and then stay on immunosuppression by transplanting a liver.
Disability is often just seen as something where the cost is literally an economic cost. What’s the burden of the person to take care of them in an institution or to take care of and make accommodations for them? If you have a kneeling bus or a ramp in the library and that sort of stuff, but you don’t get in the economist calculations often enough, just measure what it’s like to have an enjoyable life. Forget about what it costs.
There are many issues around disability that I think the world of genetic testing, even genetic engineering, neglects a little.
Counselors have been taught over the years to be neutral, and we use them frequently, particularly in academic settings. But they’re not neutral. They have a list of conditions that they look for and will counsel you on, and then there’s another broad range of things they don’t say anything about.
That boundary is shifting according to parental expectation. There are plenty of wealthy parents who I think won’t accept anything less than a perfect child. If you tell them their kid has any kind of issue, they may well start over. There are other cultures where you tell them their kid has a club foot or a minor issue, and they’re going to try and cope with it. Culture really shapes how we view. What are we going to diagnose? What are we going to treat in the U.S.?
I fear partly what determines what we’re going to diagnose is what we’ve got to test for, not necessarily whether it’s a bad thing, a good thing, a bearable thing, a cultural thing, whatever. It’s almost like, can I charge for this? Then I’m going to add it to the battery.
IPM: What has been the biggest medical moral shift over your career?
Caplan: Research ethics. When research ethics really got rolling, it was in response not to the Nazi concentration camp experiments, although the idea of informed consent came from those abuses when they were put into the court opinion. The emphasis was on informed consent.
All the way back to the Tuskegee study of the early 70s, people were put in experiments, oftentimes institutionalized Willowbrook demented Jewish chronic disease hospital kids; poorly educated Tuskegee kids in asylums; and the Iowa stuttering experiments, where they tried to figure out if they could teach kids to stutter to understand the genesis of stuttering by stressing them, and all of this culminated in the view that research is too risky and dangerous. People need protection from it.
We had a history of protectionism. It was one of these things where you’d have to be insane or inane to be a research subject. Who would want to do that? Look at what happens. People die and they get mistreated and so forth.
Probably around the time just before COVID, we were seeing a shift. It is part of the shift that is represented by MAGA and MAHA, and that is the rise of a notion of “I want more liberty and I want more ability to make my own choices.”
Today we don’t see people demanding protectionism. What we see is them demanding access. What you’re seeing in policy is more ability to give people the right to try things and more ability to say things to people. It may be very risky, but if you were to do it, we’re going to try and make that possible.
Trump is very proud of his efforts in what’s called the “right to try” space. Many states have enacted laws to try and allow people to do this. You can see special laws here and around the world to give people access to stem cells. The therapy, I think, doesn’t really have much evidence for much of anything except maybe, I don’t know, bone marrow transplants or something. But, but they’re using it for arthritis and down syndrome and autism, and who knows? The justification is “Your choice, your decision.” It’s an interesting shift.
There is a popular push, especially in the U.S., to let people take more risk, to let people take informed risks, and to let them do it. Some of the things we see today. You put them in front of an IRB 25 years ago; there is no way that they happen. Just no way.
IPM: Why have vaccines become so divisive?
Caplan: Vaccines depend upon a moral framework of public health, and public health ethics relies on a duty to your neighbor. It relies on an obligation to the community. It isn’t just about your choice. It isn’t just about freedom. It’s about responsibility. When it comes to vaccination, you have a responsibility to ensure that your neighbor’s newborn, who has no immune system and cannot be infected, or the child who has an immune disease and lacks an immune system or has undergone a transplant, or your grandmother, whose immunity is very weak, does not die from the flu, COVID, or something else.
What bioethics failed to do is articulate public health ethics. That’s what mandates are about—restrictions on liberty. That’s what quarantine is about—restrictions on freedom of movement. If you don’t see a duty to others, you’re not going to go along with any of this.
We have within the MAHA movement a real overemphasis on liberty all the time. The surgeon general of Florida said he was going to do away with all vaccine mandates for kids. That’s a bad ethic for public health. You do it that way, and you’re going to have no problem. You can drive drunk as you want anywhere you want to go and speed all you like.
There are libertarian people who would go for these things. They don’t want any government intrusion. I think it’s wrong. I think Thomas Hobbes would say you’re going to have a life that’s nasty, brutish and short if you don’t have some community ethic around in addition to choice. John Stuart Mill, who was actually a big believer in liberty, said, “Your freedom to swing your arm ends at the tip of my nose.” You can’t harm me by your choices. That’s how I say vaccination is. It’s part of the fact that we’re interconnected, that some things we do will hurt others if we don’t limit them, restrict them, and so on. In emergencies we’d have a giant plague.
Their old argument had always been vaccines aren’t safe. Today it’s about freedom. “I’m not against vaccines,” says RFK Jr. “It’s your choice.” My argument is, “Is that your choice?” If you’re in the middle of an epidemic or a pandemic, it is public health’s duty to get you all vaccinated to make this thing go away. They’re wrapped totally around the liberty and autonomy values framework and very successfully in the current climate.
The way one other group comes in is through a spokesperson, who at this point represents what I’ll call “communitarianism,” which is about caring for one’s neighbor. Ironically, it’s the Pope—both the previous one and the current one—who speaks out about AI, while the previous one focused on encouraging people to feel duties and obligations toward the weak, the poor, the vulnerable, and migrants and immigrants. Religion was ironically seen as the enemy of medicine. Now it’s providing the moral foundation and is one of the few places doing it for public health interventions.
I don’t think the public gets what public health requires, what it needs, and why it obliges them to do things they don’t normally want to do, which—okay, I understand that I didn’t like being locked in my house either, but that’s been a fear.
One other one is what I’m going to call these eugenics claims. They keep floating around that certain races are inferior or Mexicans are bringing us disease, or there are countries that are “[expletive] countries,” as the President has said, or even some of our tech bro people like Musk insisting that we have to keep an eye on breeding better children so that AI doesn’t overtake us and so on. There is really bad science behind eugenics, and I worry about it being all over the place.
IPM: What will become a hot moral battleground in the future?
Caplan: Everybody expects that the next 10, 20 years will be AI and its incorporation into healthcare, but I don’t think so. Weirdly, incorporating AI stuff into healthcare is, I think, on the whole, pretty useful. It lets you handle a lot of data, get information quickly, and reduces errors. AI skinning or AI surgery or whatever can do certain things better than the human eye or hand.
It’s not that there are no issues. It could turn out to be a huge problem as to whether we can believe any information on the internet or anything anybody posts; that’s a problem, but not within healthcare. I’m going to say “neuroscience,” and I’m going to say “modification of the brain.”
We are learning quite a bit about how the brain works, and right now we are still in the early stages of using needles to control parkinsonism, obsessive-compulsive disorder, or even obesity. That area is going to expand rapidly, raising many questions about how much you can change the brain and still be you, and about the reversibility of some of these changes.
IPM: How will history look back on this period of medical ethics?
Caplan: I think this period will be seen as the dark ages, where science was scrubbed. People were fired for legitimate work, not political reasons. That our history was rewritten to remove important examples of racism in science and medicine. Misogyny. I think we’re in a really miserable period of anti-intellectualism, again, partly spun out of COVID and its disappointments and frustrations. I do think we’re in bad times.
The post Arthur Caplan: The Right to Life, Liberty, and Pursuit of Health appeared first on Inside Precision Medicine.
STAT+: Pharmalittle: We’re reading about GLP-1 drugs and knees, FDA cell and gene therapy guidance, and more
Good morning, everyone, and welcome to the middle of the week. Congratulations on making it this far, and remember there are only a few more days until the weekend arrives. So keep plugging away. After all, what are the alternatives? While you ponder the possibilities, we invite you to join us for a delightful cup of stimulation. Our choice today is maple cinnamon French toast. Meanwhile, here is the latest menu of tidbits to help you on your way. Have a wonderful day and please do stay in touch. …
Cigna will stop covering GLP-1 weight loss drugs including Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound in its employee health plan effective July 1, Reuters reports. In a document circulated to employees on June 1, Cigna suggested those currently using the drug can choose to pay with cash through manufacturer sites or TrumpRx. The cash-pay purchases will not apply toward a deductible or the amount of spending required before enrollees can use their health coverage. The price of weight loss drugs has been falling in 2026 with the launch of Novo’s Wegovy pill and Lilly’s oral Foundayo, with prices that start at $149 per month for the lowest dose. Americans have been increasingly pushed to the cash-pay market and, at the same time, employers have been cutting back on their coverage of the drugs.
Taking weight loss drugs for at least three years could prevent thousands of knee replacements a year, The Guardian writes, citing new research. The study, published in Regional Anesthesia & Pain Medicine, found that taking GLP-1 medications for one year was associated with a 1.4% reduced risk of knee replacement surgery at the three-year follow-up point and a 2.8% lower risk after eight years. But the greatest reduction in risk was with newer weight loss drugs and longer treatment. Taking semaglutide or tirzepatide for three years was associated with a nearly 5% lower chance of needing knee replacement at the eight-year follow-up assessment.
Reduced serum cortisol, IGF-1, GLP-1, and T3 levels in medication-free children and adolescents with obsessive–compulsive disorder: a case–control study
IntroductionObsessive–compulsive disorder (OCD) frequently emerges during childhood and adolescence and has been associated with alterations in multiple neurobiological systems. Neuroendocrine pathways involved in stress regulation, neurodevelopment, metabolic signaling, and thyroid function interact closely to influence brain circuits implicated in OCD. However, studies simultaneously examining several neuroendocrine parameters in pediatric OCD remain limited.MethodsThis case–control study included 52 medication-free children and adolescents with OCD and 42 healthy controls aged 8–17 years. Psychiatric diagnoses were established using the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) according to DSM-5 criteria. Obsessive–compulsive symptom severity was assessed using the Children’s Yale–Brown Obsessive Compulsive Scale (CY-BOCS). Anxiety and depressive symptoms were evaluated using the Screen for Child Anxiety Related Emotional Disorders (SCARED) and the Children’s Depression Inventory (CDI), respectively. Serum levels of adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), Insulin-like growth factor-1 (IGF-1), Glucagon-like peptide-1 (GLP-1), relaxin-3 (RLN-3), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured using ELISA. Group differences were examined using covariance-based models controlling for age, sex, BMI percentile, anxiety (SCARED), and depressive symptoms (CDI).ResultsInitial analyses showed that children and adolescents with OCD had significantly lower serum levels of cortisol, IGF-1, GLP-1, and T3 compared with healthy controls. These differences remained significant after controlling for age, sex, BMI percentile, and the SCARED and CDI total score, with adjusted analyses showing lower levels of cortisol (p = 0.003), IGF-1 (p = 0.013), GLP-1 (p = 0.017), and T3 (p = 0.015) in the OCD group. Correlation analyses did not reveal significant associations between biochemical parameters and OCD symptom severity after correction for multiple comparisons.DiscussionThese findings suggest that pediatric OCD may be associated with alterations in several neuroendocrine pathways rather than isolated changes within a single hormonal system. Further longitudinal studies are needed to better clarify the biological basis and clinical significance of these findings.
Lilly, Ascidian Launch Up-to-$1.9B RNA Exon Editor Collaboration Targeting Inherited Kidney Diseases
Eli Lilly has expanded its genetic medicines pipeline and capabilities, agreeing to partner with Ascidian Therapeutics to develop RNA exon editors intended to treat inherited kidney diseases, through a collaboration that could generate more than $1.9 billion for the Boston biotech.
The companies have agreed to launch a global research collaboration focused on discovering and developing treatments for undisclosed monogenic kidney diseases, with the option to expand into additional targets.
At the heart of the collaboration are Ascidian’s RNA exon editors, which are designed to repair genetic instructions causing disease. A single RNA exon editor can address multiple mutations spanning multiple exons, resulting in the editing of multiple disease-causing exons simultaneously.
“What that allows us to do is to replace many exons at once, thousands of bases at a time, and use endogenous cellular machinery,” Michael Ehlers, MD, PhD, Ascidian’s president and CEO, told GEN. “We’re not editing letters in the genetic code. We’re rewriting whole chapters at the kilobase scale.
“It’s a very versatile technology to address a fairly wide-ranging set of genetic diseases, and potentially beyond as well,” he added.
Since only exons need to be replaced within the diseased protein, the exon editing payload is small enough to fit in an adeno-associated virus (AAV) or in other viral or nonviral delivery vehicles, including lipid nanoparticles.
“The therapeutic is an AAV that expresses the designed RNA exon editor. The AAV infects the target cells. The episome of the AAV dwells in the nucleus and expresses this engineered RNA molecule, our exon editor, that then conducts the trans-splicing,” Ehlers explained. “We very intentionally, across programs and things, really emphasized being a differentiated cargo company in designing these RNAs, and tried where we can to use precedented clinical delivery.”
During the transcription of DNA into RNA, noncoding introns are usually removed, while exons that remain are spliced together to form messenger RNA (mRNA) that can be translated into protein. Mutations result in malformed proteins that cause disease.
Ascidian’s RNA exon editors are designed to bind to target pre-mRNA through what the company calls a highly specific binding domain. The editor molecules are delivered as a DNA construct and transcribed into mutation-free, exon-only RNA, designed with a highly specific binding domain.
Trans-splicing process
Through a binding process called pre-mRNA trans-splicing, exon editors replace disease-causing exons, leading to what Ascidian said is expression of wild-type mRNA and protein at proper levels, in the right cells at the right time.
The exon editors are designed to address large genes or genes with high mutational variance.
“There are other excellent targets which are dominant genes, where maybe you’re uncertain whether the disease-causing mutations are dominant because they’ve got a dominant toxic gain-of-function phenotype, or they’re dominant because it’s a haploinsufficiency. The nice thing about RNA exon editing is that it doesn’t really matter to us. We simply replace the sequence with wild type, so we don’t have to worry about whether you need allele-specific knockdown in those cases, or whether you are at risk of having a haploinsufficiency phenotype,” Ehlers explained.
The exon editing approach, Ascidian said, represents a sea change for RNA therapy, which has seen treatments incorporating antisense oligonucleotides, adenosine deaminase acting on RNA (ADAR)-mediated editing, and mRNA as applied in vaccines such as those for COVID-19, and in in vivo chimeric antigen receptor T-cell (CAR-T) therapies.
“RNA exon editing is really quite different, because you can target and dodge RNAs, and instead of editing one base at a time, you’re changing big swaths of sequence at a time, and unlike a lot of other forms of editing, whether DNA or RNA—not all, but for many—there’s no need to introduce exogenous enzymes or exogenous proteins to be able to conduct the editing,” Ehlers said. “That allows Ascidian to use RNA exon editing to go after a different set of diseases, a different set of disease genes, and potentially a larger patient population.”
In kidney disease, for example, more than 60 genetic diseases are known or suspected to affect the kidneys, with over 3.5 million Americans living with severe inherited kidney disease.
“I would not say all of them are treatable, but a reasonable portion of them are, and we’re prioritizing some that are clearly important, ones where RNA exon editing is particularly uniquely suited, we believe, to addressing the underlying genetic cause,” Ehlers said.
Undisclosed targets
Ascidian has granted Lilly exclusive, target-specific rights to Ascidian’s RNA exon editing technology for undisclosed kidney disease targets. The number of targets was also not disclosed. Ascidian has agreed to lead discovery and specified preclinical activities, with Lilly agreeing to oversee additional preclinical work, clinical development, manufacturing, and commercialization. Ascidian said it retains rights to pursue other kidney-focused targets, independently or with additional partners.
Ehlers said the Lilly collaboration resulted from conversations with the pharma giant held over several years that started with Ascidian discussing its research, and over time became more focused on the companies developing the research plan and programs that they agreed to work on.
“About a year and a half ago, I would say, we kind of got really quite a bit more specific about, well, what would be some interesting areas that might fit with Lilly’s strategic interests and capabilities, where Ascidian’s technology and know-how in RNA biology and splicing biology and using RNA exon editing could apply,” Ehlers recalled.
Genetic medicine expansion
Ascidian’s RNA research and technologies fit with Lilly’s commitment in recent years to expand in genetic medicines. Lilly launched the $700 million Institute for Genetic Medicine in 2021 in Boston’s Fort Point section as part of a strategy of advancing gene and gene editing therapies, and RNA- and other nucleic acid-based therapeutics. The Institute operates in Boston and New York City, where Lilly-owned neuroscience gene therapy developer Prevail Therapeutics is based. Prevail was acquired in 2021 for up to $1.04 billion.
A year later, Lilly expanded an RNA-focused collaboration with ProQR into a potential nearly $4 billion partnership to target disorders of the liver and nervous system by applying ProQR’s RNA-editing Axoimer
platform. Lilly also snapped up another gene therapy developer, buying hearing loss-focused Akouos for up to $610 million, while last year Lilly purchased gene editing therapy developer Verve Therapeutics for up to $1.3 billion
This year, among its numerous acquisition and collaboration deals, Lilly announced plans in February to buy out circular RNA cell therapy developer Orna Therapeutics for up to $2.4 billion, targeting advancements in cell therapy, and last month acquired nonviral DNA delivery-focused drug developer Engage Biologics for up to $202 million cash.
In its latest collaboration with Ascidian, Lilly agreed to pay the biotech up to $1.9 billion, to consist of an undisclosed upfront payment and payments tied to achieving development and commercial milestones, as well as tiered royalties on global commercial sales.
Targeting Stargardt
Ascidian’s website discloses eight pipeline candidates, the most advanced of which is its sole clinical-phase candidate ACDN-01, a first-in-class RNA exon editing therapy designed to halt the progression of Stargardt disease or other ABCA4 retinopathies by targeting their genetic cause.
ACDN-01 contains a healthy copy of exons of ABCA4 RNA, designed to replace the sections of the ABCA4 RNA that contain mutations, thus creating healthy ABCA4 RNA in the retina. According to Ascidian, this is intended to produce normal ABCA4 protein that can then help clear the eye of toxic waste products. The FDA has granted ACDN-01 its Fast Track and Rare Pediatric Disease Designations.
“I anticipate this will be, by and large, the way that we will deliver exon editors. Although, in principle, it can be agnostic to the delivery method, it’s just whatever it takes to get that RNA exon editor into the cell, into the nucleus, effectively trans-splicing at the target.”
ACDN-01 is under study in the Phase I/II STELLAR trial (NCT06467344), an open-label, single ascending dose clinical study assessing the safety, tolerability, and preliminary efficacy of the treatment candidate when delivered subretinally in participants with ABCA4-related retinopathies. Last month, Ascidian said it had completed the adult dose escalation portion of the STELLAR trial and expanded the study to subjects over 12 years of age.
“We’re working as effectively as we can to get that up and going, so I’d say in the coming months,” Ehlers said when asked about the timing of the expansion.
Ascidian is also conducting an observational prescreening study called STARPATH (NCT06445322), which is designed to identify children ages 5+ and adults with Stargardt who may be eligible for future clinical trials evaluating ACDN-01.
ACDN-01 is among numerous candidates in clinical development to treat Stargardt. These candidates include genetic therapies such as:
- Ocugen’s OCU410ST (AAV5-hRORA), a modifier gene therapy that uses an adeno-associated virus serotype 5 (AAV5) delivery platform to deliver the RORA (RAR-Related Orphan Receptor A) gene to the retina.
- SpliceBio’s SB-007, a dual AAV gene therapy designed to restore expression of a functional, full-length ABCA4 protein in the retina through a protein splicing intein platform using two AAV serotype 8 (AAV8) vectors to overcome the size limitations of conventional AAVs, reconstituting biologically active ABCA4 through protein trans-splicing in target photoreceptor cells.
- VeonGen Therapeutics’ VG801, a dual AAV gene therapy enabled by the company’s vgAAV capsid and vgRNA REVeRT large-gene delivery platform, which delivers the full-length functional ABCA4 gene.
Single vector approach
Ehlers said ACDN-01 would stand out from the other genetic therapies because of its single vector approach to delivery: “I’d say the others, because the nature of the ABCA4 gene, it’s too large just for gene replacement in a single vector. All the others have to use dual vector technologies to try to address that.”
“You can imagine a single vector approach being potentially simpler and more technically feasible,” he added. “But of course, what matters is clinical data, and all these programs will play out in the clinic.”
Also in Ascidian’s pipeline: A second retinal program in lead identification phase; four neuro and neuromuscular programs in phase from lead identification to lead optimization; and two lead identification-phase programs in undisclosed “other areas.” Ascidian is also partnering with Roche to discover and develop RNA exon editing therapeutics against undisclosed neurological targets, through an up-to-$1.842 billion collaboration ($42 million paid initially) launched in 2024.
Following two years in stealth mode, Ascidian was formally launched in 2022 by venture capital firm Apple Tree Partners (ATP), which incubated the company and funded it with $50 million in Series A financing. Ehlers led that incubation as the company’s founding CEO, then chaired the company’s board while Romesh Subramanian, PhD, served as Ascidian’s president and CEO. After Subramanian left the company, Ehlers returned to Ascidian’s helm in 2023, when it closed on $40 million in Series A extension funding from ATP, with the goal of financing the development of ACDN-01 and other pipeline programs.
Since then, Ascidian has grown its workforce to about 40 people, Ehlers said.
“For a clinical stage editing company, to be in the clinic with $90 million in equity financing and have 40 people plus or minus is no small feat, and I think it has been accomplished by having the focus that we’ve had, and having just one of the best scientific teams that I’ve ever had the fortune of working with,” Ehlers said.
“We might have little bits of growth here and there to be able to support this [Lilly] collaboration, to be able to expand the technology, but I’m not anticipating substantial growth,” he added. “We’ve built the company to be efficient and focused, and we’re going to maintain that going forward.”
Lilly’s hot streak
The Ascidian collaboration continues a hot streak of collaboration and acquisition deals for the pharma giant, which is flush with cash from sales of its blockbuster glucagon-like peptide 1 (GLP-1) receptor agonist drug tirzepatide, marketed for type 2 diabetes as Mounjaro® and for obesity as Zepbound®.
So far this year, Lilly has either acquired or is acquiring 10 biotechs, most recently three privately-held developers of vaccines for infectious diseases purchased for a combined up to $3.83 billion cash—Vaccine Company for up to $1.55 billion, Curevo for up to $1.5 billion, and LimmaTech Biologics for up to $780 million.
The Ascidian collaboration is Lilly’s third partnership with a biotech, announced just this week. The other two, totaling a combined amount of up to $4.304 billion-plus, were announced with Asian partners.
Seoul-based Hanmi Pharmaceutical said Lilly had agreed to license from it the rights to develop, manufacture, and commercialize sonefpeglutide (LAPSGLP-2 analog), a Phase II glucagon-like peptide 2 (GLP-2) receptor agonist, worldwide excluding South Korea. Hanmi is now studying sonefpeglutide in a global Phase II trial (NCT04775706) in short bowel syndrome (SBS).
Lilly agreed to pay Hanmi $75 million upfront, and up to an additional $1.185 billion in payments tied to achieving clinical development, regulatory approval, and commercialization milestones, plus royalties on sales following product launch.
Beijing-based Haisco Pharmaceutical Group announced a licensing and research collaboration with Lilly to develop treatments across multiple undisclosed therapeutic areas. Haisco agreed to oversee discovery and identification of up to five “innovative target” programs, while Lilly agreed to lead IND-enabling studies, clinical development, and commercialization. Lilly will obtain exclusive global rights for some programs, as well as exclusive rights worldwide, excluding China, Hong Kong, Macau, and Taiwan, for the other programs.
Lilly agreed to pay Haisco up to $87 million in upfront and near-term payments, up to $2.967 billion in unspecified milestone payments, and single-digit tiered royalties on future product sales.
The post Lilly, Ascidian Launch Up-to-$1.9B RNA Exon Editor Collaboration Targeting Inherited Kidney Diseases appeared first on GEN – Genetic Engineering and Biotechnology News.
Top ultra-processed food researchers call for sweeping policy change: ‘The system is rigged’
The all-star lineup of ultra-processed food researchers who teamed up on a new special edition of the American Journal of Public Health have an overarching message for policymakers: “Do policy!”
That directive, offered by food politics scholar Marion Nestle during a press call ahead of the issue’s release, is accompanied by new polling that shows broad cross-partisan concerns over the health harms associated with ultra-processed foods.
A survey of 2,000 U.S. adults included in the new issue found that the overwhelming majority of Democrats, Republicans, and independents agreed that ultra-processed foods are addictive and a major cause of obesity, type 2 diabetes, and cardiovascular disease. The survey also found majority support in all parties for government interventions including testing additives for safety before they can be included in food products, banning artificial dyes, requiring warning labels, and ordering companies to reduce the amount of sugar and salt in their foods.
Opinion: How the military may be fueling eating disorders in men
As a yoga instructor in a clinic for people with eating disorders, I don’t see many straight cisgender male clients. But when I do, many have one thing in common: military service.
It is so common that, anecdotally, I would say a military background is one of the greatest risk factors for eating disorders in this population. Indeed, troops and veterans experience eating disorders and disordered eating at higher rates than civilians. For example, veterans have bulimia at rates about three times higher than civilians. Many of the male service members and veterans I work with feel their bodies will never be lean enough, strong enough, or “combat-ready” enough.