Radically different
In a rare move, nonprofit organization Blood Cancer United announced Thursday it was buying the remaining supplies of Luvelta, a discontinued investigational cancer drug.
As part of the transaction, Blood Cancer United, previously known as the Leukemia & Lymphoma Society, also will acquire the investigational new drug designation and manage the compassionate-use program for children with a rare form of blood cancer, distributing the medication to patients at no cost while supplies last.
Researchers in Japan have found that older adults with higher levels of vitamin C in their blood have a higher volume of gray matter in their brains and higher connectivity across brain regions involved in memory and attention. Published in PLOS One, their study raises the possibility of using dietary interventions to protect brain health as we age.
“What I found most fascinating about this research is that we were able to detect these subtle but significant associations between a single nutritional factor and large-scale brain networks by utilizing a robust, community-based cohort of over 2,000 older adults,” said Tomohiro Shintaku, MD, PhD, assistant professor of radiology at the Hirosaki University Graduate School of Medicine. “It truly highlights the potential impact of our everyday dietary habits on our brain structures.”
Previous research had linked diets high in vitamin C with lower risk of developing cognitive impairment in older adults. However, this study is the first to look directly at a potential link between vitamin C levels in blood and changes in brain structure and connectivity within a large participant cohort.
Shintaku and colleagues analyzed magnetic resonance imaging (MRI) scans and blood levels of vitamin C in 2,044 Japanese adults over the age of 64. They measured the volume of gray and white brain matter in each individual, as well as the connectivity between brain regions belonging to the default mode network, which are associated with important cognitive functions including autobiographical memory, future thinking, self-reference, and attention. Connectivity within the default mode network is also known to play a significant role in brain health, with lower connectivity being linked to cognitive impairment and Alzheimer’s disease, in addition to a number of psychiatric conditions including depression or schizophrenia.
After adjusting for other factors that affect brain structure and connectivity, such as age, physical activity, and education level, results showed that higher levels of vitamin C were associated with a higher volume of gray matter across several brain regions, and with higher connectivity within the default mode network.
“Our study demonstrates that higher plasma vitamin C levels are associated with better preserved structural connectivity of the default mode network, a key brain network involved in cognitive function,” said Shintaku. “This finding generates the exciting hypothesis that a diet rich in vitamin C might play a supportive role in maintaining brain health and mitigating age-related cognitive decline in older adults.”
More research will be needed to uncover the potential biological mechanisms driving this association and confirm whether there is a causal link between blood levels of vitamin C and changes in brain structure and connectivity. Going forward, the researchers plan to conduct studies looking at repeated measurements of vitamin C levels over time, accounting for additional lifestyle and nutritional factors that may influence these effects, and including cohorts with more diverse ethnicities and socioeconomic status.
The post Higher Vitamin C Levels in Blood Linked to Healthier Aging Brains appeared first on Inside Precision Medicine.
Developing truly disease-changing treatments for Alzheimer’s disease and other neurodegenerative conditions has proved challenging, with many failed trials over the last few decades. The approval of Eisai/Biogen’s monoclonal antibody lecanemab in 2023, the first such treatment to have a positive, albeit modest, impact on symptoms of Alzheimer’s disease, was therefore received with enthusiasm by many.
Critics of lecanemab and Eli Lilly’s donanemab, approved a year later for the same indication, argue that the small benefit gained from the drugs does not outweigh the economic costs, possible side effects, and burden of regular intravenous infusions.
Using a vaccine-style approach, where the treatment prompts the body to generate its own antibodies, has the potential to solve these problems. Several companies are developing active immunotherapies to target Alzheimer’s and Parkinson’s disease, as well as other neurological conditions.
“What we’re trying to do is link the antigen to a carrier and bring it into a form which mimics the pathology,” explained Andrea Pfeifer, PhD, CEO and co-founder of Swiss company AC Immune, a leading biotech taking the active immunotherapy route to target Alzheimer’s and Parkinson’s disease.
“We inject it into the immune system, and what it recognizes is the misfolded protein. So, because of that, the immune system only makes antibodies against this pathological protein.”
Although none have yet reached the market, the active vaccine-style approach potentially has a number of advantages over passive treatment with monoclonal antibodies. Importantly, fewer rounds of treatment are required. The exact dosing is yet to be determined, but it would certainly be less frequent than the regular infusions of lecanemab or donanemab that are currently prescribed. This would help reduce costs and treatment burdens for patients and their families. There is also likely to be less risk of amyloid-related imaging abnormalities (ARIA) due to the relatively slower onset of antibody generation by the body.
“If you have to take the patient every two to four weeks to get a two-hour infusion in a hospital, and then you have to wait and do imaging, it’s really burdensome,” said Pfeifer.
“After a certain while, they just don’t want to go. … They say, ‘Sorry, we believe your science, we believe everything, but we don’t want this.”
To date, most vaccine trials have enrolled people with at least some degree of Alzheimer’s or Parkinson’s disease, as preventive vaccine trials need to be large and long in duration. Theoretically, developing a preventive vaccine is a feasible approach, as many neurodegenerative diseases typically have a slow onset before noticeable symptoms appear. However, reliable biomarkers that can accurately predict disease onset have been in short supply.
This is changing, though. Last year, two blood tests that measure phosphorylated tau and amyloid ratios were approved by the U.S. Food and Drug Administration (FDA) for Alzheimer’s diagnosis. The biomarker field is less developed for Parkinson’s and other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), but things are slowly improving.
Promising mid-stage results from front-runners like AC Immune and Alzinova suggest that this pathway has merit, but whether they can succeed in larger registrational trials going forward is unclear.
“It remains to be seen how our immune system reacts. I think that when we look at the titers we see from the vaccine, they’re similar to what we get with passive immunizations. So I think there are a lot of things that point in the right direction,” said Tord Labuda, PhD, CEO of Swedish biotech Alzinova, which has an amyloid beta vaccine in development.
“Personally, I don’t think that the vaccine or passive immunization is the real challenge. The real challenge is to have the right target.”
While passive immunotherapies like lecanemab and donanemab are groundbreaking in that they are the first disease-modifying treatments for Alzheimer’s to be approved by the FDA and they slow cognitive decline by around 25%–35% over two years, these drugs can cause significant side effects such as ARIA.
This can cause brain swelling and bleeding in some people. Individuals at highest risk for some neurodegenerative conditions, such as carriers of the APOE4 gene variant, are prevented from accessing these therapies at all, as they have a higher-than-average risk of experiencing ARIA-like side effects.
Treating neurodegenerative diseases like Alzheimer’s and Parkinson’s disease when symptoms commence is problematic, as currently, there is no known method of regaining neuronal function once it has been lost.
Classic pathology studies suggest that, by the time the typical motor symptoms of Parkinson’s appear, around 50%–70% of dopaminergic neurons are already lost from the brain. Similarly, in early clinical Alzheimer’s disease, where those affected have mild dementia, hippocampal volume in the brain seen on imaging is already up to 25% lower than that of age-matched controls. This means, however good the treatment is, the patients will never regain complete function.
“There’s no way we can restore these neurons,” said Roman Kniazev, CEO of U.S.-biotech Nuravax, which is developing several different Alzheimer’s vaccines. “They are gone forever. So that is why the best strategy, and this is our motto in our company, is to not let the pathology kill the neurons.”
Researchers trying to develop new therapies for Alzheimer’s and Parkinson’s are increasingly moving towards an early or even preventive approach. The idea of a vaccine-like approach to targeting Alzheimer’s is not new. Animal work in the late 1990s showed that vaccinating against amyloid‑beta could clear plaques and improve cognition in transgenic mouse models. This led to the development of Elan/Wyeth’s amyloid‑beta vaccine, AN1792.
It entered Phase I/II trials for mild‑to‑moderate Alzheimer’s and successfully induced anti‑amyloid beta antibodies in some patients. But the study had to be stopped in 2002 because around six percent of the participants developed meningoencephalitis, linked to T cell–mediated inflammation in the brain. Despite strong amyloid plaque clearance, there was little impact on symptoms in the clinical trial participants.
Several other candidates, designed to avoid the T-cell activation seen with AN1792, have been unsuccessfully trialed over the last two decades. Although largely safe and antibody-producing, most of these programs were discontinued due to a lack of efficacy.
The field has persevered despite this, with improvements in technology, safety, biomarkers, and clinical trial design having led to a new generation of vaccine candidates that, while not yet approved, are showing good results in Phase I and II trials.
“I think what we’ve learned over the past five or 10 years from other vaccine approaches is that the next generation are those that come with a very precise approach to generating antibodies against the toxic species of a given protein for that specific neurodegenerative disease,” said Neil Warma, CEO of ProMIS Neurosciences, a U.S.-based company taking an antibody and a vaccine-based approach to treating Alzheimer’s and other neurodegenerative diseases.
“Those are really the things that make the vaccine approach much more interesting now. The sophistication of the biomarkers, the data we’ve learned from past and current products in the market, and then this ability to design and create antibodies that are highly specific to a targeted pathogenic form of the protein.”
AC Immune has three active immunotherapy candidates in Phase II: an anti-amyloid beta therapy, ACI-24, that is being developed with Takeda; an anti-tau therapy, ACF 35, being developed with Johnson & Johnson; and an anti-alpha synuclein candidate targeting Parkinson’s disease.
The company reported good results for its Parkinson’s Phase II study at the end of last year. The interim study results showed a 100% response rate and a good safety profile in people with early Parkinson’s disease. Alpha-synuclein and neurofilament light levels in the blood, as well as scores from standard movement tests, suggested that disease stabilization had occurred.
If confirmed by results from the second part of the study, this would be the first time that disease modification, rather than symptom management, has shown promise for Parkinson’s disease. It would also confirm alpha synuclein as a pathogenic contributor to the condition.
“The statistical variability was very, very small, which was a surprise to us. Every single marker, preclinical biomarker, clinical imaging, went into the same direction,” said Pfeifer. “For me, what was particularly rewarding was that there was a connection between the titers, so the antibody response in the people versus the reduction of this pathology … the alpha-synuclein versus the imaging, which showed that the neurons can be protected.”
A common theme among vaccine developers in the neurodegeneration space is precision targeting. There is a strong consensus that a lack of specificity when picking targets is likely why many trials failed to show efficacy and had significant side effect issues in the past.
Different companies or research groups back slightly different protein targets, but the experts all emphasize the importance of avoiding binding to inert plaque in the brain in Alzheimer’s disease, and of targeting toxic, misfolded proteins that are disease-specific.
“We provide the body with active immunotherapy, and then the body induces the antibodies. But what is important is that these antibodies are really specific for the pathological form,” said Pfeifer.
AC Immune is not the only company with a keen focus on tightening up targeting in this area. Alzinova is specifically targeting toxic amyloid beta oligomers with its lead candidate ALZ-101, a therapeutic Alzheimer’s vaccine.
It received a recent FDA Fast Track designation for ALZ-101 after good safety and efficacy data were reported last year from its completed Phase Ib clinical trial.
“They have shown in many in vitro and in vivo models that … when you remove these toxic oligomers using antibodies towards them, you can basically neutralize the toxicity in these extracts towards the neurons,” explained Labuda.
He added that many of the “vaccines, as well as the monoclonal antibodies, are going for the N-terminal part of the protein. … By doing that, you will target the monomers, all the fibrils, but most importantly, also the plaques. Very little will be left to bind to something else that might be more important for the disease. I think this is what we see with the current treatments on the market. There’s a lot of off-target effects … and that’s why we have these huge challenges.”
ProMIS is also targeting amyloid beta oligomers in Alzheimer’s using both a monoclonal antibody and vaccine approach. It has developed a special method with the help of artificial intelligence to develop antibodies, taking both conformational shape and protein sequence into account.
“These three-dimensional shapes don’t exist on monomers, and they’re buried in plaque. We’ve tried and tried and tried to get these antibodies to bind monomers, to bind plaque, and they really don’t, which is good,” said Warma.
“We’ve done side-by-side testing with other antibodies to see if ours is truly differentiated. … In many different studies before we got to the clinic, PMN-310, our therapeutic antibody, was the only one that bound oligomers and avoided monomers and plaque. All the others cross-reacted with everything.”
ProMIS is testing its PMN-310 antibody before moving on to the vaccine approach. “If we can come with that one-two punch to say we’ve got a drug now that can treat patients with Alzheimer’s, we’ve got the ability to detect the onset of disease pathology in Alzheimer’s, and we have a vaccine that prevents you from developing that disease, I mean, that would be a pretty powerful combination,” noted Warma.
Nuravax is aiming to address two key shortcomings of first‑generation Alzheimer’s vaccines, such as AN1792: the risk of problematic T cell-driven inflammation and uneven immune responses in older adults. Its MultiTEP‑based candidates (AV‑1959R, AV‑1980R, and Duvax) are engineered to elicit a strong, antibody‑dominant response against amyloid‑beta and tau while minimizing activation of potentially autoreactive T cells and maintaining effectiveness.
“The platform which we developed makes the vaccine highly immunogenic, and this high immunogenic feature is essential for diseases in the brain,” said Kniazev.
Kiran Bhaskar, PhD, is a professor and group leader at the University of New Mexico. He has worked on Alzheimer’s disease for many years and is also a scientific co-founder of TheraVac Biologics. He and his colleagues are developing an anti-tau Alzheimer’s vaccine that is about to start human trials.
They are also aiming to reduce risks associated with immune reactions to vaccine adjuvants, which can contribute to ARIA, and have created a vaccine that does not need an adjuvant.
“We use a strategy called a virus-like particle,” he explained. “You don’t need to expect any side effects because of adjuvants. In this way, we trick the immune system into thinking that there is a viral attack on the body. It immediately starts an immune response against the virus-like particle and also anything sticking to the surface of those virus-like particles, which in this case is pathological or phosphorylated tau proteins.”
Overall, in the trials carried out so far in the active immune therapy space in Alzheimer’s disease, rates of ARIA have been very low, which is another selling point for the vaccine approach. “We don’t expect to see ARIA in active immunotherapy because we are using the host’s own immune response system to generate antibodies. … So that way there’ll be less unanticipated immune response,” explained Bhaskar.
There is no doubt that active immunotherapies or vaccines to target Alzheimer’s and Parkinson’s disease are more advanced than they have ever been before, but they are still a long way from a mainstream rollout.
One reason the conversation has shifted is that the approval and broader use of the first anti-amyloid antibodies, for all their modest effect sizes and ARIA issues, shows that lowering the right protein species can slow deterioration. Using a more vaccine-like approach, where people make their own antibodies, does have the potential to make targeting these conditions safer, cheaper, and more accessible for patients.
But basic clinical questions remain unanswered. For example, how long vaccine-induced protection will last, how often boosters will be needed, and whether early stabilization of biomarkers and motor or cognitive scores—such as AC Immune’s interim Parkinson’s data or Alzinova’s Phase Ib Alzheimer’s study results—will translate into true preserved function a decade later.
Biomarkers are a big potential stumbling block for the development of preventive vaccines. The position is better for Alzheimer’s disease; the FDA’s approval of two blood-based Alzheimer’s biomarkers now gives developers a way to find people with silent pathologies without relying solely on positron emission tomography imaging. But there is still a lot more to do on this front, particularly in diseases like Parkinson’s, ALS, or other neurological or neurodegenerative diseases where less is known.
“We need better and safer treatments, but it’s also linked to having the right biomarkers, because if you have a risk factor, it doesn’t mean necessarily that you have the disease,” said Pfeifer. “These biomarkers are still not very well established. … The goal is absolutely to go to preclinical, and preclinical will require these biomarkers. If you ask me what is needed most in Parkinson’s right now, [it] is definitely to have better biomarkers.”
A second stumbling block for companies that want to develop vaccines that can effectively immunize people against neurodegenerative disease is that clinical trials of vaccines in populations of people with no symptoms have historically been large, expensive, and time-consuming—something out of reach of most biotechs without significant outside investment.
ProMIS and others are hoping that the efficacy of their therapeutic antibodies will boost their vaccine pipeline in the future. “If we show that it works in Alzheimer’s, then a similar approach should work in these other diseases,” said Warma. “Since it’s an almost identical process for vaccines, it also shows proof of concept for this whole wave of vaccines coming behind it.”
For now, active immunotherapies promise something that is more modest than true disease prevention but still crucially important. Namely, cheaper, less burdensome, and potentially safer ways to target the same disease biology as today’s monoclonal antibodies, ideally years earlier in the process.
The post Stopping Neurodegeneration in Place with Vaccines appeared first on Inside Precision Medicine.
Remotely monitoring patients after they have been released from the hospital for serious infections does not reduce their risk of readmission, particularly for older adults, a randomized trial suggests.
The findings, released simultaneously in JAMA Network Open and at the Critical Care Reviews annual meeting in Belfast, emphasize the importance of studying potentially beneficial care models in real-world scenarios.
Remote monitoring involves the use of resources such as smartphone-based questionnaires, internet-connected scales, or blood pressure monitoring to allow patients to leave hospital.
These enable clinicians to monitor health from afar, while acting on alerts to ensure timely care.
While patients might prefer this type of care, the trial suggested that remote monitoring should be re-evaluated and individually tailored after acute care for sepsis and lower respiratory tract infections.
It did not increase the days patients spent at home and did not support U.S. federal agency efforts to reduce hospital readmissions by reimbursing remote monitoring.
“Health systems, insurers and policymakers all want to reduce hospital readmissions, and most patients prefer to recover safely at home,” explained lead researcher Sachin Yende, PhD, from the University of Pittsburgh.
“Remote monitoring has been held up as a solution, is reimbursed by the Centers of Medicare & Medicaid and its use has grown. But, aside from a few conditions, there’s a dearth of high-quality data to show it reduces readmissions.”
In an attempt to source this information, Yende and team conducted a complex trial in 1286 adults, with a median age of 63 years, who were recovering at home after hospitalization for sepsis or lower respiratory tract infections at 19 institutions. Of these patients, 32.6% received intensive care.
Participants were randomly assigned to one of four remote monitoring strategies or usual care.
Usual care generally involved a phone call from a nurse after discharge followed by continuing management from a primary care physician. The remote monitoring interventions consisted of short or long health questionnaire with standard or enhanced clinical response teams.
The standard response involved nurses who responded to alerts highlighted in the questionnaires together with coordinated care involving the patient’s primary and specialty clinicians.
Enhanced care included certified registered nurse practitioners with palliative care expertise who could coordinate some of the care response and also access social workers.
The primary endpoint was days at home at 90 days after discharge.
The trial showed that remote monitoring programs with high- or low-intensity questionnaires combined with a nurse response team or a nurse practitioner-led response team did not increase the time spent at home.
At least one readmission occurred among 37.8% of patients in the control group, receiving usual care.
This compared with 39.7% in patients receiving the shorter questionnaire and standard response team, 44.2% for those receiving the long questionnaire with standard clinical response, 37.3% receiving the shorter questionnaire but enhanced response team, and 36.3% for those receiving the long questionnaire with enhanced clinical response.
These differences did not reach statistical significance.
However, among patients aged 65 years and older, the remote monitoring programs did reduced time spent at home and increased readmission rates compared with usual care.
In this older age group, both the standard and enhanced response groups had fewer home days compared with usual care, with corresponding cumulative odds ratios of 0.56 and 0.67.
“These findings support reevaluating and tailoring remote monitoring in post–acute care following sepsis and lower respiratory tract infection to support further alignment with patients’ needs and desire for personalized monitoring,” the researchers concluded.
The post Remote Monitoring Benefits Unclear After Hospitalization for Serious Infection appeared first on Inside Precision Medicine.
Scientists at the University of California San Diego have reported the results of a genome-wide association study in rats that identified key biological drivers of cocaine addiction. Using a genetically diverse group of nearly 900 rats to map genetic markers associated with compulsive drug use, the researchers uncovered a potential new therapeutic target that resides in the liver rather than in the brain.
Current research in this field often focuses on the brain, but the UC San Diego team’s findings suggest that how the body metabolizes cocaine may be just as critical in determining whether somebody develops an addiction.
“Finding a liver-based enzyme that shapes cocaine-taking behavior was a real ‘aha’ moment for us,” said Olivier George, PhD, a professor of psychiatry at UC San Diego School of Medicine. The George lab led the addiction behavioral studies that provided the foundation for the research. “It reminds us that addiction isn’t only in the brain. It’s a complex puzzle involving how the entire body processes the drug.”
George is co-corresponding author of the team’s published paper in Nature Communications, titled “Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats.”
Cocaine use disorder (CUD) has a strong genetic component, the authors noted. “Twin studies estimate the heritability of cocaine dependence to be as high as 70%, a finding supported by recent comprehensive reviews,” they wrote. GWAS have also uncovered a significant heritable component, the team continued, with single nucleotide polymorphism (SN)-based heritability estimated at 27-30%. However, scientists have struggled to pinpoint the specific genes that make certain individuals more vulnerable to addiction.
“The paucity of significant and replicated associations for CUD limits our understanding of this disorder, hampering our ability to identify novel pharmacological targets,” the investigators added. Co-corresponding author Abraham A. Palmer, PhD, professor of psychiatry at UC San Diego School of Medicine, who led the project’s intensive genetic modeling and analysis, further commented, “Identifying those genes in an important goal, because drugs could then be developed to target those genes, shifting genetically susceptible people to become more like genetically resistant people.”
To investigate further, the team carried out a GWAS in nearly 900 outbred Heterogeneous Stock (HS) rats—a model system capable of mimicking the vast genetic diversity found in human populations. By using HS rats the team was able to capture the critical differences between individuals who are genetically susceptible to addiction and those who are naturally more resistant. “Prior work has established the phenotypic diversity of HS rats across a broad range of addiction-relevant behaviors, including cocaine self-administration,” the researchers commented.
“The extended access model allowed us to characterize escalating intake, increased motivation to take the drug, and compulsive-like behavior despite negative consequences.” In addition to the GWAS results the researchers carried out a range of secondary analysis strategies to uncover what they describe as novel genetic drivers of cocaine self-administration behaviors.
Analyzing millions of genetic markers in each animal, the team discovered six major genetic regions linked to addiction-like behaviors, such as the escalation of drug intake and the time elapsed between doses. The researchers identified in the rats a specific group of carboxylesterase genes that are orthologous to the human CES1 gene, which are responsible for creating the enzyme that metabolizes cocaine. The study found that variations in these genes are closely linked to how frequently and compulsively rats self-administered the drug.
The findings also replicated a known genetic link found in humans (Trak2), providing a vital translational bridge between animal research and human medicine. This replication strengthens the argument that the biological pathways identified in the lab could eventually lead to real-world therapies. “Genes associated with CUD in humans remain limited, however our GWAS identified one gene (Trak2) that has also been identified by human GWAS of CUD, and the novel identification of Ces1 offers a fresh avenue for future studies,” they stated.
The collective findings suggest that by targeting the enzymes that metabolize cocaine with medicines, scientists might be able to alter how the drug affects the body, potentially reducing its addictive impact. In their paper they concluded “Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases.”
Palmer said, “This work showcases the power of long-term, team-science collaboration that pairs experts in rodent behavior with quantitative geneticists. A decade of coordinated effort across multiple cohorts and federal partners made possible a discovery that no single lab could achieve alone.”
First author Montana Kay Lara, PhD, a postdoctoral researcher at UC San Diego School of Medicine, who helped bridge the gap between the study’s behavioral and genetic components, said, “Seeing the Ces1 signal validate a hypothesis that has been circulating for decades is incredibly exciting. It gives us a concrete target to test whether changing how cocaine is metabolized can blunt the drive toward compulsive use.”
The research team is now moving into the next phase of the project, which involves investigating exactly how these genetic mutations change function of the enzyme. They also hope to use the study’s extensive Preclinical Addiction Biobanks—collections of blood, urine, brain and other tissue samples—to identify biological markers that could one day help predict an individual’s risk of developing a substance use disorder.
The researchers hope that by leveraging this resource, they and other scientists working in this space will be able to translate genetic discoveries into diagnostic tools and new treatments that can help stabilize individuals struggling with addiction.
The post Potential Cocaine Addiction Targets Identified Through Genetic Mapping in Rats appeared first on GEN – Genetic Engineering and Biotechnology News.
Background: Depression is a prevalent mental disorder, and it remains one of the leading causes of disability in Canada and globally. Mobile app–based physical activity interventions may offer an effective and accessible treatment option for individuals with depression who cannot or prefer not to access supervised exercise programs. Objective: This study aims to investigate the feasibility, acceptability, and proof of concept of a 9-week, theory-guided, app-based physical activity promotion intervention (MoodMover) developed for people with depression. Methods: We conducted a single-arm, pre-post study from November 2024 to May 2025, following the phase IIa: Proof-of-concept and phase IIb: Pilot and Preliminary Testing of the Obesity-Related Behavioural Intervention Trials model. Physically inactive adults who either self-reported a diagnosis of major depressive disorder or reported at least mild depressive symptoms, operationalized as a minimum score of 5 on the Patient Health Questionnaire, 9-Item, were recruited. The intervention spanned 9 weeks, with the first week serving as a run-in period and including a 15-minute orientation session on the first day. Participants were instructed to use the MoodMover program, delivered via the Pathverse app. Feasibility was assessed based on 4 primary criteria: recruitment, adherence, usability, and retention. Proof-of-concept was evaluated by assessing changes in physical activity behavior and depressive symptoms over the intervention period. Results: From November 2024 to March 2025, 32 of the 51 adults who met eligibility criteria consented to participate in this study, resulting in a recruitment rate of 63%. Twenty-eight participants completed baseline assessments, with a mean age of 39.8 (SD 13.4) years. A total of 21 participants attended the orientation session and received the intervention. Retention, adherence, and usability rates were 57% (16/28), 67% (14/21), and 50% (8/16), respectively. Regression analyses found that age consistently associated with app engagement, usability, and satisfaction. Two-tailed paired tests indicated significant pre-post changes in self-reported moderate to vigorous physical activity and depressive symptoms across the 75%, 85%, and 95% CIs. Among participants with clinically elevated depressive symptoms at baseline (Patient Health Questionnaire, 9-Item ≥10), 75% (9/12) achieved a clinically meaningful reduction in symptom severity. Conclusions: Our findings suggest that MoodMover holds potential for promoting physical activity behavior among individuals with depression and supporting depression management at scale. However, the feasibility of the tested version remains suboptimal. Necessary modifications (eg, improvements to enhance the accuracy of step tracking) should be implemented and reevaluated before progressing to a more rigorous efficacy trial. Trial Registration: ClinicalTrials.gov NCT06573125; https://clinicaltrials.gov/study/NCT06573125
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Background: People with intellectual disability experience rates of mental illness up to 3 times higher than the general population, yet face significant barriers to care, including limited clinician expertise, diagnostic overshadowing, and exclusion from key mental health services. Electronic mental health interventions have demonstrated effectiveness in the general population and may address these barriers for people with intellectual disability by providing accessible, tailored treatment. Objective: This study examined the ability of Healthy Mind, a self-guided, web-based transdiagnostic mental health program designed specifically for people with borderline to mild intellectual disability, to reduce symptoms of anxiety and depression and improve functioning in people with intellectual disability. Methods: In a single-arm uncontrolled design, Australian residents aged ≥16 years with a diagnosis of borderline or mild intellectual disability, and mild-to-moderate symptoms of depression or anxiety on the Anxiety, Depression, and Mood Scale (ADAMS) were recruited online and offered access to Healthy Mind. Assistance from a nominated supporter was optional. Primary outcomes were symptoms of depression and anxiety (ADAMS). Secondary outcomes were psychological distress (Kessler Psychological Distress Scale [K10]) and functional impairment (World Health Organization Disability Assessment Schedule 2.0 [WHO-DAS]). Outcomes were assessed at baseline, 8 weeks, and 3 months. In total, 80 participants (mean age 27.8, SD 7 y; n=37, 46% female; n=39, 49% identifying as Aboriginal and/or Torres Strait Islander) enrolled; 61% (n=49) nominated a supporter. Data were analyzed using multilevel models with random intercepts for participants. Results: No significant changes were found in ADAMS depression or anxiety scores from baseline to postintervention or follow-up. Similarly, no significant effects were found for K10 or WHO-DAS scores, except for an improvement in K10 scores between baseline and 3 months when controlling for cognitive functioning (n=15). Having a supporter was associated with lower baseline distress but did not moderate treatment effects. Engagement with Healthy Mind was low; 42.5% (n=34) did not access the program, and among those who did, the median number of completed modules was 7 (IQR 3-11). Greater module completion was associated with slightly higher WHO-DAS scores post intervention. Conclusions: This trial did not demonstrate significant improvements in mental health or functioning associated with Healthy Mind, likely due to low engagement, reduced statistical power, and the absence of a control group. Nonetheless, the study demonstrates the feasibility of recruiting and retaining people with intellectual disability in fully online trials and highlights the urgent need for strategies to improve engagement, including gamification, personalized content, and integrated social features. Electronic mental health remains a promising avenue for addressing the substantial mental health service gap for people with intellectual disability. Trial Registration: ANZCTR ACTRN12620000113954; https://tinyurl.com/2ecdmde8 International Registered Report Identifier (IRRID): RR2-10.3390/ijerph18052473
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Background: The use of large language models (LLMs)–powered chatbots has reshaped how people seek information and advice, including for emotional and mental health support. While LLMs can offer scalable support, their ability to safely detect and respond to acute mental health crises—including suicidal ideation, self-harm, and violent thoughts—remains poorly understood. Progress is hampered by the absence of unified mental health crisis taxonomies, annotated benchmarks, and empirical evaluations grounded in clinical best practices. Objective: We addressed these gaps by introducing (1) a unified taxonomy of 6 clinically informed mental health crisis categories; (2) an evaluation dataset of over 2000 user inputs drawn from 12 publicly available conversational mental health datasets, classified into crisis categories; and (3) an expert-designed protocol for assessing response appropriateness. We also used LLMs to automatically identify crisis-indicative inputs and conducted an auditing study of 5 LLMs to evaluate the safety and appropriateness of their responses. Methods: We developed a taxonomy of mental health crisis categories informed by clinical experts and established literature. From over 239,000 mental health–related user inputs collected from 12 Hugging Face datasets, we curated 2252 examples (206 for validation, 2046 for testing) covering all taxonomy categories. We evaluated 3 LLMs on their ability to classify inputs into crisis categories, selecting the model with the strongest agreement with human annotators as the judge to label the test set. We then audited 5 LLMs on their ability to generate safe and appropriate responses to the 2046 test examples. Response quality was measured using a clinically informed 5-point Likert scale (1=harmful and 5=fully appropriate), relying on an LLM-as-a-judge validated against human expert feedback. Results: Several LLMs exhibited high consistency and generally reliable behavior when responding to explicit crisis disclosures, but significant risks remain. A nonnegligible proportion of responses was rated as inappropriate or harmful, particularly in the self-harm and suicidal ideation categories. Substantial performance differences were observed across models: gpt-5-nano and deepseek-v3.2-exp achieved very low harmful response rates, whereas gpt-4o-mini, Llama-4-Scout-17B-16E-Instruct, and grok-4-fast-non-reasoning generated markedly higher rates of unsafe outputs. All models exhibited systemic weaknesses, including poor handling of indirect or ambiguous risk signals, reliance on formulaic responses, and frequent misalignment with user context. Conclusions: These findings underscore the urgent need for enhanced safeguards, improved crisis detection, and context-aware interventions in LLM deployments and highlight the central role of alignment and safety engineering—beyond model scale or openness—in determining crisis response reliability. Our taxonomy, dataset, and evaluation framework lay the groundwork for ongoing research in artificial intelligence–driven mental health support, helping to minimize harm and protect vulnerable users.
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Although gene therapy has shown promise for the treatment of Duchenne muscular dystrophy (DMD), the limitations of viral vectors have proven challenging to clinical advancement. Now, a new treatment platform delivered skeletal-muscle-targeted full-length DMD mRNA systemically in a murine model of DMD, successfully restoring the production of dystrophin, and dramatically improve muscle strength, endurance, and function in vivo.
The approach uses allogenically engineered targeting extracellular vesicles (DMD t-EVs)— which offer distinct benefits over current viral-based gene therapies, including reduced side effects and the ability to transfer the entire DMD gene. The researchers engineered the EVs with special tags that directly target skeletal muscles after being injected into the bloodstream. The work also demonstrated the safety and biocompatibility of DMD t-EVs in non-human primates, supporting their translational potential.
“Our new platform overcomes the limitations of current viral-based gene therapies, allowing for the delivery of full-length mRNA, restoring wild-type translation of dystrophin and significantly improving muscle function,” said Betty Kim, MD, PhD, in the department of neurosurgery at UT MD Anderson. “We are highly encouraged by these results, which provide a blueprint for mRNA-loaded EVs as a next-generation therapeutic strategy.”
The study, published today in Nature Biomedical Engineering, is entitled, “Skeletal-muscle-targeted non-viral delivery of full-length DMD mRNA for Duchenne muscular dystrophy.”
DMD is a severe genetic disorder caused by mutations in the DMD gene that prevent dystrophin production, which helps stabilize and protect muscle cells during contractions in healthy individuals. Without dystrophin, the muscles become easily damaged, leading to eventual inflammation and cell death. DMD primarily affects males, with symptoms such as delayed walking and waddling usually appearing in early childhood. As the disease progresses, it leads to loss of walking ability, scoliosis, heart problems and eventual respiratory failure.
Because DMD is the longest known gene in the human genome, current viral-based gene therapies are unable to carry the full length. These limitations result in the loss of the gene’s full function and prevent challenges like dose-limiting toxicities, immune reactions, and other adverse reactions including death.
These side effects have resulted in the removal of at least one Food and Drug Administration-approved gene therapy from the market and are why researchers have been trying to develop alternative ways of safely delivering the full-length DMD gene.
In this study, the researchers loaded the full-length DMD mRNA into EVs that were engineered to specifically target and bind to skeletal muscles. Injection of these mRNA-loaded EVs led to an increase in dystrophin protein expression as well as improved muscle strength and function in preclinical models, with no serious side effects.
Importantly, the treatment stayed on target inside of skeletal muscles and did not trigger any immune responses or toxicities commonly seen with viral-based treatments, even after repeated dosage.
Future studies are needed to determine the full safety of EV-mediated mRNA platforms for clinical trials, including whether they can be delivered to cardiac muscles, as heart conditions are commonly seen in advanced disease. However, based on these results, the authors point out this could be a promising method beyond treating Duchenne muscular dystrophy, also potentially serving as a broader “protein restoration” or cellular reprogramming platform.
“Given that we are now able to replace very large proteins, this platform- and disease-agnostic approach could potentially open doors far beyond rare genetic disorders and traditional gene therapy applications,” Kim said. “It’s possible this could ultimately enable restoration of proteins lost not only through inherited diseases but also from acquired or degenerative processes, including cancer, autoimmune disorders, neurodegeneration, fibrosis and other chronic diseases.”
The post New mRNA Delivery Platform Restores Muscle Function in DMD Models appeared first on GEN – Genetic Engineering and Biotechnology News.