Tag: Academic research

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Cyclana Bio Is Exploring the Extracellular Matrix to Treat Endometriosis

Despite an estimated 190 million women and girls around the world living with endometriosis, a chronic and painful gynecological condition, no disease-modifying therapy has yet been approved to treat it. Léa Wenger, PhD, and her colleagues at Cyclana Bio are aiming to fix this.

Endometriosis occurs when endometrial tissue grows outside the uterus, causing inflammation, pain, and sometimes scarring and fertility problems. Although this condition was historically neglected in terms of research and development, Cyclana is now one of a small but growing group of companies trying to develop more effective endometriosis treatments. After completing a veterinary degree, Wenger shifted away from clinical practice when she discovered a passion for biomedical research during her PhD at the University of Cambridge. During this time, Wenger was diagnosed with endometriosis, which led her to co-found Cyclana Bio in 2024 with Kevin Chalut, PhD, who was her colleague at Altos Labs at the time.

The company joined the Babraham accelerator program last year and has already raised an oversubscribed £5 million ($6.8 million) pre-seed round. Wenger spoke to Inside Precision Medicine’s senior editor, Helen Albert, about her inspirations, career, and what she and her colleagues are hoping to achieve at Cyclana.

 

Q: What inspired you to become a scientist?

Léa Wenger, PhD
Léa Wenger, PhD

Léa Wenger: I was always very curious as a child. What drove me directly to science, rather than going for any other subjects, was my desire to be a vet. I wanted to be a vet and knew vets needed to know about science, so I decided to learn all the science I could. The irony of that was that I didn’t end up practicing a single day of veterinary medicine, but it got me into the doors of institutions where they teach you veterinary medicine in a way that was very scientific and research-driven. I really discovered a passion for science at that point, a passion for actually understanding things that we don’t know. I was exposed to this idea of driving knowledge where it isn’t present, and that was really what got me excited about research. That’s when I effectively shifted from the veterinary medicine career to the more traditional biomedical research route.

 

Q: What made you decide to go into biotech rather than staying in academia?

Wenger: I think the frustration I had in academia was that the system was set up to do a one-person, one-project type of research. That can be fun in some ways, but for me, it didn’t really address impact in the way that I really wanted it to. I wanted to feel like I was working towards creating discovery, translating it, and being able to improve patient lives. I just felt that biotech was a better conduit for that because it was based on faster-moving collaborative teamwork.

I was working in neurodegeneration at the time and on organoid models made of 3D stem cell-derived complex architectures. Organoid models are incredibly good at reproducing human development. But when you’re looking at neurodegenerative diseases that happen with age, it’s a lot harder. Aging in a dish is really hard to reproduce.

Cyclana Bio scientists
Cyclana Bio scientists working in the LiveLabs laboratory, from left to right, Kevin Chalut, PhD, cso and co-founder, Léa Wenger, PhD, ceo and co-founder,
Siiri Salooma, PhD, founding scientist, and Tom Wyatt, PhD, founding scientist.

It was at exactly then that I wanted to go down this research route in more detail that Altos Labs opened in Cambridge. The company had a thesis of “Let’s try and do real discovery science, deep, groundbreaking science,” but in a biotech environment where you’re much more collaborative. That really attracted me at the time, and so I applied to work there after my PhD. Luckily enough, they took a chance on me and believed in me.

I loved it and I learned a huge amount. Not just in terms of how you build discovery programs from the ground up, but also how you work in a team, how you focus, and how you align incentives in biotech. I think it completely shifted my mindset away from simple academic curiosity to, “How do we drive that curiosity towards impact as quickly as possible?” The bar, in my opinion, is somewhat higher than in academia because you’re not just saying, “Is this good enough to publish?” You’re saying, “Is this a therapy? Is this actually good enough to put into a human and help them and not harm them?”

 

Q: What made you decide to found Cyclana Bio?

Wenger: I was in an epigenetics lab within Altos, and my co-founder was actually one of the group leaders there working on the extracellular matrix. The more I worked with him, the more I realized how massively important it is in guiding how cells behave. You can get completely different responses from a cell depending on what environment it’s in. I got really interested in that interface between the epigenetics, the gene level regulation, and the [extracellular] matrix.

I was doing a lot of discovery science there, but during that time, I also developed endometriosis. I was in my mid-to-late 20s when my symptoms started, and they got worse very quickly. Like every scientist who gets diagnosed with a condition, I nerded out on the disease. In my spare time, I downloaded all the data and looked into what research was there, and very quickly realized that there wasn’t much information available.

There’s not much that we know about the disease and how it happens. People are still debating the causes and drivers of endometriosis. That was interesting and another area of unknown, which has always been what I was attracted to. I’d always been passionate about women’s health, but never really had the opportunity to do something about it.

There’s an easy, non-invasive way of getting access to cells to study endometriosis because menstrual fluid is built and shed every month from your endometrium. It’s built and shed in healthy women, in women with endometriosis, and in women with other conditions. On top of that, biopsies are actually way more common in gynecology than in a lot of other conditions. So I realized this was a huge opportunity to do this tissue-level discovery that we were so passionate about, but for a cause that I really believed in, in a field that was unknown.

I spoke to the CEO at Altos at the time and explained what I wanted to do. He was supportive and thought it was an interesting idea, but ultimately, the indication didn’t align with the priorities of Altos—of looking into age-related diseases. So that’s when we left and started Cyclana Bio.

 

Q: How easy was it to start the company?

Wenger: We were very lucky in that we got into the Babraham accelerator program very quickly, last May. That was important because not only did it give us validation that someone had actually picked us and said this is a good idea, but it also gave us lab space and access.

We did take quite a bit of a risk. Both my co-founder and I left without having raised funding or grants to start the company. For a short while, we were living off our savings and also paying for some very preliminary science and our first scientist to try and get some data going. That was in May [2025], but quite quickly, we got a bit of traction. By July, we had our first investment term sheet because we started fundraising immediately. Then by September, we were oversubscribed. We finalized the closing in October–November for a £5 million pre-seed round.

I think along the way, we basically just had to assume it was going to happen. We were building the company as if we had the money already, although we were always very open with Tom [Wyatt], the scientist who joined us first, about how much funding we had when he joined.

We’re nine people now and have some amazing scientists who have joined the team, including a great CTO who was also at Altos beforehand. We are still growing as we speak. It’s funny how science brings so much more science.

 

Q: What are you trying to achieve at Cyclana?

Wenger: Our main aim is to get at least one therapy that’s truly disease-reversing to the clinic. Based on a lot of research, we know that the extracellular matrix can guide how cells respond. It can act as a sink for particular signal factors. Sometimes it can sequester or deliver things like growth factors or inflammatory signals, but it also massively changes how the cell is interacting with its neighbors.

It’s a key component of a positive runaway effect that happens in lots of chronic inflammatory diseases and in some cancers. A lot of the time, when trying to develop treatments, we focus on the cells and whether we can stop that inflammation. What we think is, if you don’t address problems with the matrix, you are not going to cure the disease. You’re effectively just going to mitigate the side effects, and this matrix is going to act like a memory of the disease. This means that if you stop the treatment, it comes back because the matrix issue hasn’t been solved.

We think that that’s a big element of what’s going wrong with endometriosis. Lesions are removed surgically and then they come back. We really think the diseased extracellular matrix is very much driving the pro-inflammatory phenotype, and that if we don’t address that, we don’t actually get to the point where we are curing the disease. We want to see if we can effectively reverse the phenotypes and if we can effectively get to a cure by stopping this recurrent feedback loop.

We haven’t settled on an exact target or modality yet. We’re exploring a few different targets, and I think based on exactly what mechanism we want to go after, we will determine what the best modality is. We want to be sure about the science, very sure about the target, and then make that target work.

 

Q: Where does precision medicine come into your strategy?

Wenger: Our overall strategy is based on how we see endometriosis as a whole, but I think endometriosis hopefully won’t be viewed like that much longer. We hope that there’s going to be much better stratification and classification of the disease, because it manifests very differently in different women.

Although we think the extracellular matrix might be a common mechanism, we’re building a research platform where we will hopefully find out for sure because we’re collecting data. We’ve got an ongoing observational clinical study where we’re collecting biopsy tissue, menstrual fluids, clinical data, and blood from women, either with or without endometriosis.

We’re collecting that data, looking at the tissue, the proteins, and the architecture, but also isolating cells to test in our models. Then, when we start perturbing with particular interventions that we think might reverse the disease’s impact on the matrix or have different effects on the cells, we might start seeing patterns as to which types of women with endometriosis respond well to different treatments.

It’s going pretty well so far, thanks to our clinical collaborators and participants who have donated samples. Menstrual fluid is a very good way of getting samples from seemingly healthy women, because they don’t need to go to the doctor, [they] just send us a sample. We are also collecting tissue biopsies during routine gynecological procedures to minimize invasiveness and inconvenience.

So far, there’s lots of variability, which was what we expected and which is why we want to collect [samples from] a high number of donors. Not because we think that variability is noise, but because variability is signal. It can tell us more about the nuances of the disease in these different manifestations.

 

Q: What has the experience of being a CEO and biotech founder been like so far?

Wenger: It’s definitely been a steep learning curve. I think that’s also why it’s been so fulfilling, because I do love being in an environment where I’m not complacent, where I’m always learning.

To some extent, because we had so much freedom at Altos to drive our own projects, I had exposure already to the pure project management side of science, so that didn’t seem quite as much of a step up.

Obviously, there’s a huge business, commercial, and legal dimension that I never had thought about before. But I have been trying to learn as much as I can, as quickly as I can, from others. One thing that the biotech field is quite good at is volunteering information. You go to any sort of networking event, or you meet someone from the industry, and they are often very willing to talk to you about what they’re interested in, but also about what you’re doing, and give any advice they might have.

I’ve met many people who have helped me along the way and who have shared their opinions with me. I walked in expecting academia to be way more collaborative than the biotech industry, but actually, I’ve been very pleasantly surprised with my experience.

 

Q: Can you share any key learning experiences from the last year?

Wenger: If you have scientific training or you can think in a scientific way, going into the field of business or building a company is somewhat similar. There’s lots of information and lots of alternative paths that you can take, just like in scientific discovery, and there is differently weighted evidence as to which paths are the best ones to take. Once you have a certain amount of information, you can then take the best educated guess. That’s how I’ve gone about building the company. For example, when I started, I was told by a friend, “If you’re starting a biotech, you’re going to need to raise venture capital.” They gave me a book called Venture Deals, which is a very good book that explains how funds work. I read that book and felt I was better equipped to talk to people at the fundraisers. I think the first thing I’d say is, when going into any sort of field, try to really understand how and why that field exists and what are the structures that define its environment. Then you can put context into how people work. As a first-time founder, you might think, “I’m going to find investors, and if they believe in me, they’ll invest.” But there’s so much more to running a venture capital fund. Those things are important to know when framing your discussion.

Something I would do differently is not do everything at once. I left my job, started the company, started the science, started building the network, and started fundraising at the same time. There was always this pressure when I was meeting people that I also had to get them to invest. I think looking back on it, if I could start over, I probably would have spent a few more months trying to build my network and understanding the field better before I started having those investment conversations. It still worked out for us, we still raised funds, but it was stressful. Networking events were very high stakes!

 

Q: How has the endometriosis space changed in recent years?

Wenger: Gedeon Richter purchasing the Celmatix portfolio and backing FimmCyte are very good signs that people are trying again. I think endometriosis has been plagued by failures in clinical trials, and I think now we’re finally seeing some non-hormonal options being tested, which makes me hopeful. Some will fail, some will succeed, and the successes will drive more interest and availability of funding and hopefully, more successes in the future. I’m really looking forward to seeing the results from some of those clinical trials because I think the more solutions we have for women, the better.

 

Q: Is funding in the overall field of women’s health changing for the better?

Wenger: Absolutely. I think the funding environment is more open to women’s health. I think that’s been helped by the World Economic Forum and McKinsey Health Institute driving the message of value there. There is excitement, I think, and more funding, especially privately.

I’m not sure about public funding. I do think that on the public funding side, we have a trend of saying, “We should fund women’s health, let’s look for quick wins.” I think that’s a bit of a problem with any field that’s been somewhat left behind, once we realize that we need to bring it back. The risk will be funding the wrong things or putting too much of the money into solutions that may not be revolutionary because they don’t have the foundational science to back them up.

It can also be easy to get stuck in the valley of death between seed and late-stage funding. But I do think that there are incredible scientists moving into the field, and there are some great companies starting up. So even if there is this bias towards pre-seed or seed funding, you only need a couple of those companies to have some really promising data, and they will be funded. The bar might be higher than in other fields, but if you produce groundbreaking discoveries, there will be money.

 

Q: What advice would you give other new founders starting to build their companies?

Wenger: Just follow your gut and your dream. That’s the most important thing. I started Cyclana because I thought this needed to happen and we needed to look into endometriosis. I thought it was a bit hypocritical of me to think we needed to do something and not do it, despite having the training and the skills to try and find a solution. If you really believe something needs to happen in the world, startups are the best way to feel like you are driving that change and contributing to seeing the change that you want to happen. Whether it succeeds or not, you won’t wake up thinking, “What am I doing this for?” You’ll just be thinking, “I really hope that we don’t fail!”

 

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.

The post Cyclana Bio Is Exploring the Extracellular Matrix to Treat Endometriosis appeared first on Inside Precision Medicine.

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Higher Vitamin C Levels in Blood Linked to Healthier Aging Brains

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. 

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Stopping Neurodegeneration in Place with Vaccines

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.

Andrea Pfiefer
Andrea Pfiefer, PhD
CEO and Co-founder
AC Immune

“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.

Alzinova’s ALZ-101
ALZ-101 – Alzinova’s disease-modifying vaccine candidate for Alzheimer’s disease

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.

Tord Labuda
Tord Labuda, PhD
CEO, Alzinova

“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.”

Taking a more active approach to immunotherapy

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.

Neil Warma
Neil Warma
CEO, ProMIS Neurosciences

“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.

Staining of neurons in the brain
Staining of neurons in the brain from Neil Cashman’s lab-1.

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.”

Better targeting to improve safety and efficacy

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
Kiran Bhaskar, PhD
Professor
University of New Mexico

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.

syringe and vaccine bottle
Credit: Ake Ngiamsanguan / iStock / Getty Images Plus

Overcoming challenges on the road to the clinic

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.

surgical glove pointing at a brain scan image
Credit: Martin Philip / iStock / Getty Images Plus

“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.

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Potential Cocaine Addiction Targets Identified Through Genetic Mapping in Rats

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.

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App-Based Physical Activity Intervention for Individuals With Depression (MoodMover): Single-Arm, Pre-Post Proof-of-Concept and Feasibility Study

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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A Self-Guided Web-Based Transdiagnostic Mental Health Program for People With Intellectual Disability: Single-Arm Trial

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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Between Help and Harm: An Evaluation Study of Mental Health Crisis Handling by Large Language Models

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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New mRNA Delivery Platform Restores Muscle Function in DMD Models

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.

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Acceptability, Usability, and Perceived Quality of Care of a Digital Decision Support System in Tele–Primary Health Care in Sindh, Pakistan: Sequential Explanatory Mixed Methods Pilot Study

Background: Primary health care (PHC) delivery in Pakistan is constrained by persistent workforce shortages, which are further exacerbated by the attrition of trained female physicians following marriage or childbirth. Telehealth platforms, such as Sehat Kahani, have emerged as one response to this gap, enabling female physicians to provide remote primary care from home. Within this model, a digital decision support system (DDSS) was recently piloted for selected febrile illnesses to strengthen clinical decision-making. However, evidence on how such systems are perceived by female PHC providers in low-income and middle-income country settings remains limited. In particular, there is limited understanding of how perceived usefulness, ease of use, and perceived impact on quality of care shape the early adoption of DDSS within tele-PHC workflows. Objective: This pilot study aimed to explore the acceptability, perceived ease of use, and perceived quality of care associated with a DDSS among female PHC providers delivering teleconsultations through a large-scale telehealth platform in Sindh, Pakistan. Methods: An exploratory pilot study using a sequential explanatory mixed methods design was conducted. Quantitative data were collected through an online survey of female health care providers (N=30) across 5 telehealth clinics using the DDSS. The survey assessed experiences related to DDSS utilization, usability, technical facilitation, satisfaction, and perceived diagnostic and treatment accuracy. This was followed by 3 focus group discussions to further examine facilitators and barriers to DDSS use. Survey data were analyzed descriptively, and qualitative data were analyzed thematically. Qualitative findings were used to explain and contextualize quantitative patterns. Results: Survey findings indicated frequent integration of DDSS into routine teleconsultation practice, with 43.3% (n=13) of providers using the system multiple times per day. DDSS was primarily used alongside clinical judgment (n=16, 53.3%) rather than as a standalone decision-making tool. Half (n=15, 50%) of participants reported confidence in the accuracy of DDSS-supported recommendations, while 46.7% (n=14) reported occasional reassessment of system outputs. Usability perceptions were generally positive, with 50% (n=15) reporting moderate satisfaction and 46.7% (n=14) finding the system easy to navigate. Qualitative findings contextualized these patterns, highlighting that DDSS enhanced decision-making confidence, supported care in unfamiliar clinical domains, and promoted standardized practice, while also revealing concerns about algorithm completeness and workflow burden. Conclusions: This pilot study suggests that DDSS embedded within telehealth platforms is acceptable to female PHC providers and can support clinical decision-making in resource-constrained PHC settings. By providing early implementation evidence from a real-world tele-PHC setting in a low- or middle-income country, this study contributes context-specific insights to inform iterative refinement and responsible scale-up of DDSS-enabled care models.
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Fighting Antimicrobial Resistance with Biomaterials and Phages

Antimicrobial resistance (AMR) is a significant global health threat, with its impact felt across all regions of the world.1 According to the World Health Organization (WHO), AMR is responsible for an estimated 700,000 deaths annually worldwide, and this figure is projected to rise to 10 million deaths per year by 2050 if current trends persist.

Notably, the number of deaths attributable to AMR in many countries surpasses those caused by diabetes, kidney diseases, digestive disorders, and other non-communicable diseases. AMR has profound implications for clinical practice, affecting the management of infections across various healthcare settings. Here, we will discuss recent advances using novel biomaterials and phage for combating AMR.

Wounds, in particular, are susceptible to colonization by AMR bacteria, complicating wound healing and increasing the risk of serious complications such as sepsis and amputation, which in turn exacerbates the chronic wound burden. Chronic wounds impact the healthcare system because of their increasing prevalence and cost. The rapid growth of AMR further limits the effectiveness of standard antibiotic therapies, necessitating the use of more potent and costly antimicrobial agents, which may have adverse effects and contribute to further resistance development.

The most common bacteria isolated from chronic wounds include species of Staphylococcus (47–55%), primarily S. aureus and S. epidermidis, P. aeruginosa (25–33.6%), Acinetobacter spp., Enterococcus faecalis, and Enterobacteriaceae such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp.2 Many of these bacteria have developed persistent AMR, such as methicillin-resistant S. aureus (MRSA). They are highly resistant to commonly used antibiotics and, therefore, limit treatment options for wound infection. To combat the growing threat of infected wounds with AMR bacteria, Han and colleagues devised a creative approach to directly degrade proteins responsible for bacterial growth.3

UDP-N-acetylmuramoyl-L-alanine-D-glutamate ligase (MurD) is a prime target for combating antibiotic resistance in bacteria as it catalyzes the synthesis of peptidoglycan, the predominant structural component in bacterial cell walls. Han et al. developed a bacterial nanoinducer (bacNID) designed to specifically degrade MurD, effectively inhibiting the growth of both Gram-positive and Gram-negative bacteria.

Two critical, interconnected challenges

“Our paper addresses two critical, interconnected challenges in global public health and antibacterial therapy: 1) The crisis of antibiotic resistance. Bacteria rapidly evolve resistance to conventional antibiotics through mechanisms such as membrane permeability changes, target mutations, enzymatic inactivation, and efflux pumps; and 2)  The failure of the traditional drug development model. The pharmaceutical industry faces a >95% failure rate in developing new antibiotics. Even when new drugs are found, bacteria often develop resistance quickly, and many candidates suffer from poor pharmacokinetics, systemic toxicity, and an inability to selectively target bacteria over healthy host cells,” says Guangjun Nie, PhD, senior author of the paper and professor at the National Center for Nanoscience and Technology, Beijing, China.

Nie adds that by moving away from the “one-target-one-drug” inhibition model, their study solves the problem of how to kill bacteria without giving them a chance to evolve resistance. “It achieves this by hijacking the bacteria’s own protein degradation machinery to destroy essential proteins such as MurD that are necessary for cell wall synthesis.”

The team first conjugated MurD-targeting peptides (pMurD) on gold nanoparticles, alongside the addition of a rapidly degradable SsrA peptide tag. The role of the SsrA tag is to bind MurD, thereby “tricking” the bacterial ClpXP protease into degrading MurD. Gold nanoparticles function as a peptide delivery vehicle that is taken up directly by the bacteria to circumvent the potential membrane permeability barrier. In this way, bacNID can destroy MurD, which is needed to synthesize the cell wall, leading to bacterial death.

bacterial research
The rapid growth of AMR limits the effectiveness of standard antibiotic therapies, necessitating the use of more potent and costly antimicrobial agents, which may have adverse effects and contribute to further resistance development. [10174593_258/Getty Images]

The team showed that bacNID was able to specifically inhibit model Gram-positive and Gram-negative bacteria with a dose-dependent degradation profile while exhibiting low cytotoxicity towards nontargeted mammalian cells. BacNID also specifically targeted MurD while sparing other Mur ligases. This approach can also be used with other nanoparticle vehicles, such as platinum, making it a versatile method for universal inhibition of diverse AMR bacteria.

To improve mechanistic understanding, the team utilized a variety of techniques and discovered that bacNID-treated bacteria suffered from cell wall damage, leading to leakage of a significant amount of DNA and ATP. Interestingly, compared with conventional antibiotics, treatment with bacNID did not lead to the formation of resistance after sustained treatment.

Using an in vivo infected skin wound model, the authors showed that bacNID treatment not only reduced infection burden but also promoted better wound healing outcomes, including greater skin cell proliferation, neo-angiogenesis, and lower inflammation. To expand the applicability of their method, bacNID was also tested in a S. aureus-infected nonhealing keratitis model and S. typhimurium-induced colitis model, showing great efficacy in both diseases.

“While our current study focuses on MurD, a major future step is to apply the bacNID platform to degrade other essential bacterial proteins. Readers can expect the team to develop bacNIDs against different targets in various pathogenic bacteria (e.g., targeting virulence factors or other metabolic enzymes). Future iterations of bacNIDs may incorporate stimuli-responsive nanotechnology (e.g., pH or enzyme-sensitive linkages) to ensure that the degradation-inducing activity is activated only within the specific microenvironment of the infection site, further minimizing off-target effects,” says Nie.

“We will also conduct more in-depth mechanistic studies to definitively elucidate why targeted protein degradation fails to induce the antibiotic resistance observed with conventional therapies.”

Guangjun Nie, PhD, professor at the National Center for Nanoscience and Technology, Beijing, China, with his team of scientists in the lab. [Guangjun Nie]
Guangjun Nie, PhD, professor at the National Center for Nanoscience and Technology, Beijing, China, with his team of scientists in the lab. [Guangjun Nie]

Trick bacteria with bacteria

Owing to an aging population, there is a rise in the use of implants, but these implants are prone to the formation of bacterial biofilm. The extracellular polymeric material in biofilm is known to reduce antibiotic penetration while creating an immunosuppressive environment, leading to impaired antimicrobial responses. In particular, orthopedic implants provide a conducive habitat for hematogenous bacteria for growth and formation of biofilm. Yang and colleagues hypothesized that bacteria that cause implant infection can be repackaged as drug carriers to penetrate biofilm for intra-film drug delivery.4

“Genetically modified bacteria have emerged as a promising delivery platform for diverse biomedical applications, ranging from cancer immunotherapy to infectious disease treatment. However, the clinical translation of current live bacterial biotherapeutics remains hindered by two major bottlenecks: unresolved in vivo safety concerns and the requirement for sophisticated species-specific genetic engineering. By exploiting the inherent life cycle of biofilms, our chemically primed bacterial triggers enable localized drug release deep inside biofilm structures, achieving effective biofilm eradication across genetically distinct bacterial and fungal infection models,” says Wei Tao, PhD, senior author and professor at Harvard Medical School.

The team first prepared bacteria by subjecting them to calcium chloride to increase membrane porosity and enhance their ability to uptake exogenous drugs like antibiotics. Ultraviolet radiation was then used to deactivate the bacterial membrane repair mechanism, creating irreversible membrane pores. They found that the modified bacteria, i.e., tricker, was able to migrate and thrive in biofilm and eventually, release exogenous drugs that are otherwise, challenging for delivery.

As a biofilm matures, surrounding bacteria are known to be attracted to and integrated into it. The team first labeled their tricker bacteria with a fluorescent dye and found that the bacteria were integrated throughout the biofilm with 80% coverage. However, a caveat is that the integration is most effective if the tricker and biofilm bacterial species are the same. The team discovered that while modified S. aureus can penetrate the core of S. aureus biofilm in 60 minutes, modified E. coli barely penetrates S. aureus biofilm. Likewise, modified E. coli can penetrate the core of E. coli biofilm, while modified S. aureus can penetrate E. coli biofilm with a much lower efficiency. Once in the biofilm, the chemically modified and inactivated bacteria were found to lyse, especially at hypoxic and acidic conditions.

Besides preventing antibiotic penetration, biofilm can also release bacterial-derived materials that suppress the immune system, particularly macrophages. For instance, it is well-characterized that S. aureus biofilms can bias macrophages towards an anti-inflammatory M2 phenotype, characterized by impaired antimicrobial peptide production, elevated arginase-1 (Arg-1), and attenuated inducible nitric oxide synthase (iNOS) expression. Interestingly, Yang and colleagues found that tricker bacteria were able to modify the metabolic states of the biofilm, resulting in enhanced production of I-arginine via iNOS to generate nitric oxide to improve bacterial clearance capacity.

Using an in vivo model of subcutaneous implant infection, the team found that there was an observable increase in mature dendritic cell and M1-like macrophage activation in the lymph nodes. The amount of memory B cells and antibodies with antimicrobial immune memory functions was also increased. After primary bacterial inoculation and intervention, the team reintroduced MRSA and found that 86% of treated mice rejected MRSA while all mice in the control group succumbed to the infection. This finding suggested that treatment with tricker bacteria was able to evoke innate and adaptive immune system endogenously for better control of AMR, with potential for bacterial-specific systemic memory to prevent relapse.

Finally, the strategy was tested in a murine bone infection model. By tracking cytokine levels and tissue histology, the team showed that their strategy was biologically safe. An MRSA rechallenge to the contralateral knee also led to a significant drop in biofilm burden in treated mice, providing convincing evidence of immune memory.

“To advance its clinical translation, the antibacterial efficacy of this approach will be further validated in large animal models, including rabbits, pigs, and dogs. This strategy exhibits enormous potential for future clinical translation of personalized antibacterial therapeutics, which enables highly efficient and precise treatment by profiling patient-derived pathogens and designing tailored “tricker” bacteria. Moreover, the current approach is adaptable to polymicrobial infections. Future work will also explore the feasibility of combining modified bacteria with other antibacterial agents or functional materials to optimize therapeutic performance,” adds Tao.

Wei Tao, PhD, professor at the Harvard Medical School (far right, first row) and his research team. [Wei Tao]
Wei Tao, PhD, professor at the Harvard Medical School (far right, first row) and his research team. [Wei Tao]

Using phage cocktail in clinical trials

Biofilm-related vascular graft infections (VGIs) are a major therapeutic challenge attributing to persistent, antibiotic-resistant bacteria residing in retained grafts. Graft explant is not always possible due to patient factors and surgical technical challenges. To effectively preserve the graft, treatment of VGI is typically a prolonged course of parenteral antibiotics followed by long-term suppressive antimicrobial therapy. Yet, graft survival rate is low, and recurrent infection is common.

Phages are viruses that specifically infect bacterial cells and can cause bacterial lysis. They have been shown to be active against both biofilm-forming bacteria and can even enhance antibiotic activity by eliciting phage-antibiotic synergies to combat AMR. Chung and colleagues made use of a phage cocktail to treat a 36-year-old female patient with refractory P. aeruginosa mediastinitis and vascular graft infection.5

“Our paper addresses key translational barriers to effective treatment of VGI caused by multidrug-resistant, biofilm-forming pathogens. Firstly, antibiotic failure in biofilm-associated infections as VGI pathogens embedded within biofilms exhibit marked tolerance to antibiotics, leading to persistent infection and relapse despite prolonged therapy. Secondly, escalating AMR as resistant subpopulations emerge under antibiotic pressure, further limiting treatment options in already complex infections. Thirdly, the lack of timely, personalized therapy as conventional phage therapy workflows are slow, making timely intervention difficult in acute or deteriorating cases.

Next, unpredictable phage–antibiotic interactions, such as phage-antibiotic synergy, are not reliably identified or optimised in routine clinical workflows. Finally, fragmented clinical-laboratory integration, as there is limited integration between real-time microbiology, pharmacology, and clinical decision-making to enable adaptive therapy,” says Andrea Kwa, PhD, senior author and associate professor at the SingHealth-Duke-National University of Singapore Medical School.

The team set up a multidimensional evaluation workflow to identify the most suitable therapeutic phages from the Singapore Phage Repository. Screening began with phage susceptibility testing of the four P. aeruginosa clinical isolates using spot and plaque assays, before other assays to identify the most potent cocktail. As phages are highly immunogenic when administered intravenously, the team also performed systemic inflammation monitoring and found that the patient tolerated the phages well.

The team found that their phage cocktail was able to restore antibiotic susceptibility by altering the efflux capacity of the bacteria. This positively impacted the antibiotic options for the patient. For instance, fluoroquinolone susceptibility was restored, resuscitating its use as an oral suppressive antibiotic for the long-term management of VGI.

Kwa adds that building on this proof-of-concept, her team’s next phase focuses on scaling, standardization, and integration of timely bespoke phage–antibiotic therapy into routine clinical practice. “Our key future directions include scaling up of rapid-response phage platforms, such as expansion of phage libraries/repositories with well-characterized, clinically ready phages with faster turnaround for matching and deployment, overcoming current procurement delays. We will also develop standardized precision workflows for phage susceptibility testing and phage–antibiotic synergy testing.  Our team will also enhance regulatory and translational readiness of our technology for GMP-compatible production pipelines to enable scalable clinical deployment.”

AMR is a serious healthcare issue affecting the world. With the rising use of antibiotics in farms and clinical settings, this problem needs to be taken seriously. Unfortunately, the development of antibiotics is slow and mostly unsuccessful, thus requiring a new approach for society to effectively treat AMR. Biomaterials offer a new avenue to deliver tricker bacteria into biofilm to improve intra-film drug delivery and to activate the suppressed immune system, while also inhibiting intra-bacterial growth mechanisms. Phage is also becoming a popular option, especially for personalized medicine, and this therapy may see even greater efficacy when combined with biomaterials such as hydrogel to improve its delivery and reduce systemic immunogenicity.

References

  1. Bertagnolio S, Dobreva Z, Centner CM, et al. WHO global research priorities for antimicrobial resistance in human health. Lancet Microbe. Elsevier Ltd. 2024;5(11). doi:10.1016/S2666-5247(24)00134-4
  2. Uberoi A, McCready-Vangi A, Grice EA. The wound microbiota: microbial mechanisms of impaired wound healing and infection. Nat Rev Microbiol. Nature Research. 2024;22(8):507-521. doi:10.1038/s41579-024-01035-z
  3. Han L, Huang W, Pan X, et al. Utilizing nanoinducers for precision degradation of bacterial protein to mitigate antibiotic resistance. Nature Communications . 2025;16(1). doi:10.1038/s41467-025-66221-w
  4. Yang C, Saiding Q, Chen W, et al. Chemically modified and inactivated bacteria enable intra-biofilm drug delivery and long-term immunity against implant infections. Nat Biomed Eng. Published online January 16, 2026. doi:10.1038/s41551-025-01600-8
  5. Chung SJ, Liu Y, Thong S, et al. Timely bespoke phage-antibiotic combination to treat refractory Pseudomonas aeruginosa mediastinitis and vascular graft infection. Nat Commun. Published online January 9, 2026. doi:10.1038/s41467-025-68136-y

 

 

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