Lentiviral vectors are gaining momentum not just as ex vivo tools but as potential in vivo therapeutic platforms. But with that shift comes a number of manufacturing challenges, including higher doses, tighter control of impurities, greater batch consistency, and scalable processes to meet both clinical and commercial needs.

In this GEN Podcast, two experts from SK pharmteco, a global CMO, address these challenges and lay out some best practices that guide the manufacture of lentiviral vectors with the requisite purity, robustness, and economic feasibility required for widespread clinical adoption..

Podcast Guests:

Tatiana Nanda, PhD
CTO, Cell and Gene Therapy
SK pharmteco

Mardhani Aparajithan
Director of Manufacturing,
Science and Technology
SK pharmteco

Produced with support from:

The post Enabling <i>In Vivo</i> Lentiviral Therapies: Manufacturing Strategies to Improve Purity, Scalability, and Clinical Readiness appeared first on GEN - Genetic Engineering and Biotechnology News.

Many current therapies benefit patients with the most common disease-associated mutation, F508del. However they often have little effect on patients who harbor other types of mutations. For example, some patients have a mutation named 1717-1G>A, which is relatively common but doesn’t have any approved therapies due to being a splicing mutation that results in little to no protein production. In fact, “about 10% of people with CF do not qualify for any of the available CFTR modulator therapies, particularly those people with severe splicing mutations that result in frameshifts and the formation of premature termination codons.”

The 1717-1G>A mutation is the target of the therapy described in the paper, which was written by scientists from the University of Trento and their collaborators elsewhere. Specifically, the team developed an “adenine base editing strategy to efficiently correct the 1717-1G>A mutation,” they wrote in Science Translational Medicine. “By harnessing the SpRY-­ ABE9 system, which we delivered as optimized RNAs for both the base editor and single guide RNA (sgRNA), we achieved functional correction in patient-derived models.” 

Furthermore, the scientists note that they opted to use base editing rather than strategies like base editing because it has the advantage of “typically higher nucleotide modification efficiencies and a streamlined system requiring only the editor and an sgRNA” and because it has been used in other CF studies. 

Using their ABE9 base editor and modified CRISPR-Cas9 tool, the scientists report successfully editing up to 30% of target DNA in human embryonic kidney cell lines and patient-derived airway epithelial cells with minimal off-target effects. It also corrected the mutation in intestinal organoids derived from CF patients as evidenced by restored CFTR activity. 

Additional studies are needed, especially in animals, to fully assess the effectiveness of potential therapy but early results are promising. Overall, the approach achieved an editing efficiency of 13%. Prior studies showed that 10% efficiency may be enough for functional recovery. The results suggest that the therapy could benefit the subset of patients whose disease is caused by 1717-1G>A.

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Headed by Giulio Ciucci, PhD, and Serena Zacchigna, MD, PhD, at the ICGEB Cardiovascular Biology Laboratory, the scientists say the findings shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to new cancer therapies based on mechanical stimulation. First author Ciucci, together with senior author Zacchigna and colleagues reported on their findings in Science, in a paper titled “Mechanical load inhibits cancer growth in mouse and human hearts.” In their report the authors concluded “Collectively, the data presented in this work provide evidence that mechanical load in the heart inhibits cancer cell proliferation, likely explaining the low incidence of cardiac tumors.”

Heart cancer is very rare in mammals, but as the authors noted, “The mechanisms that protect the heart remain elusive.” The adult human heart in addition has a limited capacity for self-renewal, with cardiomyocytes regenerating at roughly 1% per year. “This suggests that the same mechanisms that halt the proliferation of cardiac cells could also inhibit the growth of cancer cells in the adult heart,” the authors continued. One proposed explanation for this loss of cardiomyocyte proliferative capacity lies in the intense mechanical demands placed on heart tissues, which must continuously pump blood against significant resistance. “We hypothesized that it could similarly hamper the proliferation of cancer cells in the heart,” the investigators reported.

Using a genetically engineered mouse model, Ciucci et al. first showed that the heart is remarkably resistant to cancer-causing mutations, even when potent oncogenic changes were introduced. To understand why, the authors developed a transplantation model in which the heart’s mechanical workload could be reduced. By grafting a donor heart into the neck of a compatible mouse, they created a “mechanically unloaded” organ, one that remained perfused with blood but did not bear physiological strain. “To assess the contribution of mechanical load to the low incidence and growth of cancer in the heart, we used a model of in vivo cardiac unloading by heterotopically transplanting a donor heart into the neck of a recipient syngeneic mouse,” they explained.

According to the study findings, mechanical forces within the tissue reshape the cancer cell genome’s regulatory landscape, influencing whether cells can proliferate. Central to this process is Nesprin-2, a protein that transmits mechanical signals from the cell surface to the nucleus. “Nesprin-2, a protein known to mediate mechanotransduction from the cytoplasm to the nucleus, emerged as a key molecule sensing mechanical forces operating in beating hearts and translating them into reduced cell proliferation,” the scientists reported.

Nesprin-2, a component of the LINC complex, senses the mechanical microenvironment of the heart and functionally alters chromatin structure and histone methylation, reducing gene activity linked to tumor cell proliferation. When Nesprin-2 was silenced in cancer cells, those cells regained the ability to grow in the mechanically active environment of the heart, forming tumors. “Silencing of Nesprin-2 in lung cancer cells prior to their implantation in the heart in vivo restored the capacity of the cells to proliferate in the presence of physiological mechanical load, resulting in the formation of large tumors,” the authors stated.

The team noted that their collective results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to new approaches to cancer therapy. “This offers fundamental insights into the biology of cell proliferation within the myocardium, and additionally, the mechanical stimuli that operate in a beating heart could be exploited for the development of a mechanical therapy for cancer.”

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GEN: How do you define regenerative medicine?

Buchheit: Many people think of regenerative medicine as growing new organs, but I define it more broadly as any therapy that improves tissue health or function. With that definition, we can include platelet-rich plasma (PRP), stem cells, and autologous conditioned serum (ACS). These approaches aim to enhance tissue health and improve function.

GEN: The field is promising, but also sometimes criticized as overhyped. Which areas deserve that criticism, and which have gained credibility through clinical validation?

Buchheit: Some criticism is valid, especially around stem cells. We’ve all seen claims over “miracle” stem cells that regrow cartilage. In reality, while these cells can be therapeutic, they typically don’t survive long after injection. Instead, they work by activating the body’s immune-based healing mechanisms. They can improve tissue health, but they’re not the miracle cures they were once portrayed to be.

On the other hand, therapies like PRP and ACS have gained credibility when properly applied and studied, particularly in musculoskeletal conditions.

GEN: How do you incorporate regenerative medicine into your practice?

Buchheit: I focus on patient function—what people can do now and what they want to achieve. Then tailor therapies accordingly. I prioritize treatments with strong evidence. One example is ACS, also known as the Regenokine* program. It’s highly standardized and supported by over 20 years of research in osteoarthritis, sciatica, and radiculopathy.

I also use PRP, which can be effective, but only when properly dosed. That’s been a major challenge since there are many ways to prepare PRP. We now know that dose matters. For example, treating knee osteoarthritis typically requires close to 10 billion platelets. At our clinic, we measure platelet counts before and after preparation to ensure accuracy, something often not done enough or at all.

GEN: Where did these approaches originate, and how widely are they used?

Buchheit: ACS originated in Germany in the 1990s with Dr. Peter Wehling. It was initially developed as an alternative to steroids for treating sciatica. The process involves incubating whole blood under controlled conditions, which stimulates the release of anti-inflammatory proteins, growth factors, and exosomes.

It became popular as patients, including athletes, traveled to Germany for treatment. Today, it’s available in the United States, though still more common in Europe. We now better understand how it works. Our research shows that exosomes play a key role in long-term benefits. If you remove them, effectiveness drops significantly.

GEN: Your new book Healing Joints and Nerves—who is it for?

Buchheit: It’s written for patients and a broad audience. I focused on authoring a book on regenerative medicine based on scientific accuracy and depth. I wanted to create a resource that explains these therapies clearly and truthfully—what they can and cannot do. It took over six years to complete. The book covers the history of stem cells and concludes with ACS, including both research and my personal experience with it as an avid runner and bicycle rider.

GEN: You often mention “good” vs. “bad” inflammation. What’s the difference?

Buchheit: Chronic inflammation is harmful. It damages tissue, drives pain, and contributes to diseases like osteoarthritis. But acute, controlled inflammation is essential for healing. It triggers the body’s repair processes. Exercise is a good example. It creates cycles of inflammation and recovery that make us stronger. Regenerative therapies aim to harness this same mechanism.

Interestingly, suppressing inflammation too aggressively can backfire. Studies show that patients who take anti-inflammatories after acute injuries may have a higher risk of chronic pain. Repeated steroid injections can also worsen joint damage over time.

GEN: Does all PRP work for osteoarthritis?

Buchheit: No. PRP must contain a sufficient platelet dose to be effective. Research shows that below approximately three billion platelets, it’s unlikely to work. Above four billion, effectiveness improves, and near 10 billion provides optimal results.

A practical tip: patients should ask how much blood is drawn. If only 10 mL is used to produce PRP, it’s mathematically impossible to achieve a high dose. Proper preparation typically requires 60–120 mL. Patients should also ask whether platelet counts are measured.

GEN: Please talk a bit more about Regenokine.

Buchheit: The program is based on ACS, enhanced through a controlled incubation process. This stimulates cells to release anti-inflammatory proteins, growth factors, and exosomes. Treatment typically takes roughly a week. Patients often come to the clinic for that duration. We’ve seen strong results in osteoarthritis and spine conditions, especially in patients who haven’t responded to other treatments, including stem cells.

GEN: What about safety, efficacy, and durability of results?

Buchheit: Outcomes vary by patient, but the primary goal is restoring function—whether that’s walking a dog or running a marathon. My approach is to stay as evidence-based as possible. That’s critical in a field where there is some overpromise or poorly validated treatments.

There are real concerns regarding product quality, sourcing, and transparency in some parts of the market. We need to know exactly what we’re using, how it works, and what evidence supports it. That’s how regenerative medicine will continue to advance responsibly.

Thomas Buchheit, MD, founded the Triangle Regen Medicine and Biologics Center in Chapel Hill, NC, to bring a range of regenerative therapies to patients. He now serves as an adjunct associate professor at Duke and continues to work with scientists at the Center for Translational Pain Medicine.

Buchheit began studying nerve injury pain and served as chief of pain medicine at Duke University Medical Center. He investigated the immune basis of pain relief following injury and the mechanisms behind regenerative therapies, including platelet-rich plasma, stem cells, and autologous conditioned serum. He has led several studies funded by the NIH and the Department of Defense.

*Regenokine was developed by Peter Wehling, MD, in Germany, originally in the 1990s. It utilizes a patient’s own blood to create a serum rich in anti-inflammatory proteins, particularly the interleukin 1 receptor antagonist (IL-1Ra), which helps reduce inflammation and promote healing in joints and tendons. The treatment is used for conditions like osteoarthritis and has gained popularity among athletes seeking pain relief. While it has shown promise in small studies, it is not yet FDA-approved and is not covered by insurance in the United States.

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Fay Lin, PhD, senior editor, technology at GEN, and Jonathan D. Grinstein, PhD, North American editor at Inside Precision Medicine, discuss how AI is increasingly embedded across cancer research areas, from organoid models to pathology. Yet challenges such as data integration, longitudinal patient tracking, and clinician confidence continue to hinder its impact on patient outcomes.

Watch the full discussion below for a clearer view of the trends, tensions, and inflection points in AI shaping the future of cancer research:

The post AACR 2026 Video Update: Cancer Research Edges Toward an AI-Driven Era appeared first on GEN - Genetic Engineering and Biotechnology News.

Patients with advanced platinum-resistant ovarian cancer whose disease had progressed on standard therapy experienced clinical benefit when treated with the investigational antibody-drug conjugate (ADC) QLS5132.

This finding is according to results from a Phase I clinical trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held in San Diego.

Patients diagnosed with platinum-resistant ovarian cancer face both a poor prognosis and limited treatment options, explained Tao Zhu, MD, chief physician and vice president of Zhejiang Cancer Hospital in China, who presented the study.

Zhu and collaborators tested an investigational ADC, QLS5132, which targets the protein CLDN6. QLS5132 combines a CLDN6-targeting monoclonal antibody with a cytotoxic payload, topoisomerase-1 inhibitor, at a drug-to-antibody ratio of 8:1. CLDN6, Zhu said, makes an ideal target as a protein with very high expression on the surface of ovarian cancer cells and minimal cell-surface expression in healthy tissues.

“The primary purpose of this first-in-human study was to evaluate the safety, tolerability, and pharmacokinetic profile of QLS5132 in patients with platinum-resistant ovarian cancer and determine the recommended Phase II dose for future clinical development,” Zhu said. “Additionally, we aimed to assess preliminary antitumor activity to establish an early signal of clinical benefit in this heavily pretreated population with limited options.”

The Phase I, single-arm, dose-escalation trial enrolled 28 patients with a median age of 57.5 who had been diagnosed with advanced platinum-resistant ovarian cancer and who had experienced progression while on standard therapy. The research team administered QLS5132 as an intravenous infusion every three weeks at dose levels of 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.6 mg/kg, and 6.4 mg/kg.

Treatment-related adverse events (TRAEs) occurred in 26 (92.9%) patients, with nausea, anorexia, anemia, and weakness occurring most frequently. Nine (32.1%) patients experienced TRAEs of grade 3 or higher, and of those grade ≥3 TRAEs, seven were instances of hematological toxicity. No TRAEs led to treatment discontinuation or death, and no patients experienced interstitial lung disease, ocular toxicity, or febrile neutropenia, Zhu said.

After a median follow-up of 2.2 months, nine patients had a partial response at various dose levels. Two of these partial responses occurred in patients who had no detectable CLDN6 expression.

Across all dose levels, 18 evaluable patients experienced an objective response rate of 50% and a disease control rate of 94.4%. When calculated for the 17 evaluable patients who had received dose levels ≥3.2 mg/kg, the objective response rate and disease control rate rose to 52.9% and 100%, respectively. These responses to QLS5132 occurred irrespective of patients’ CLDN6 expression levels at baseline.

“The most encouraging finding from our study was that QLS5132 demonstrated compelling antitumor activity in patients with platinum-resistant ovarian cancer, with an objective response rate exceeding 50%,” said Zhu. “Equally important, at the potential recommended Phase II dose, we observed a favorable safety profile with no reported cases of interstitial lung disease, ocular toxicity, oral mucositis, or febrile neutropenia.”

Zhu also noted that, though more research would be needed to confirm, preliminary data indicated antitumor activity from QLS5132 regardless of CLDN6 expression levels—which, he said, could expand its potential as a treatment option to a broad cohort of patients with platinum-resistant ovarian cancer.

Zhu acknowledged that further research would be needed to fully understand why QLS5132 can have anticancer effects in patients with undetectable CLDN6 tumoral expression. But he suggested the phenomenon may have a few explanations, including tumor heterogeneity, as well as a potent bystander effect resulting in antitumor efficacy even in cells with low or no CLDN6 expression.

“These findings support the advancement of QLS5132 into Phase III studies, with the goal of providing a much-needed new treatment option for these patients,” said Zhu.

Some limitations of this study include a small sample size and an exploratory single-arm design.

This study was funded by Qilu Pharmaceutical. Zhu discloses no conflicts of interest.

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CAR T cell therapies have revolutionized outcomes for certain blood cancers, yet their impact on solid tumors has lagged. The field has long wrestled with T cell exhaustion—a state in which engineered cells lose their potency and fail to sustain an anti‑tumor response.

At this year’s AACR annual meeting in San Diego, researchers from the Perelman School of Medicine at the University of Pennsylvania presented first‑in‑human Phase I data pointing to a possible solution. Their novel “KIR‑CAR” T cell therapy demonstrated a favorable safety profile and early signals of activity across multiple solid tumor types.

The investigational therapy, SynKIR-110, represents a departure from traditional CAR T designs. Rather than using a single-chain receptor, the therapy is modeled after natural killer (NK) cell receptors and uses a “multi-chain” architecture.

This design separates tumor recognition from activation, effectively creating an intrinsic “on-off” mechanism. The T cell remains in a resting state until it encounters its target, at which point the receptor components assemble to trigger an immune attack.

“The KIR-CAR design provides a natural ‘on-off’ mechanism, which helps avoid the problem of T cell exhaustion,” said Janos L. Tanyi, MD, PhD, principal investigator of the study. “The CAR turns on when it finds its target, kills it, and then rests, rather than constantly burning energy.”

This contrasts with conventional CAR T cells, which remain continuously active and can become depleted over time, limiting their effectiveness—particularly in the more complex microenvironment of solid tumors.

The Phase I dose-escalation trial enrolled nine patients with advanced, mesothelin-expressing cancers, including ovarian cancer, mesothelioma, and cholangiocarcinoma. These patients had limited treatment options, having received an average of four prior lines of therapy.

Although the primary goal of the study was to assess safety, early signs of efficacy were observed. Disease stabilization was reported in four patients, and one patient in the highest dose cohort achieved an ongoing partial response.

“These are cancer types that have never had an approved cell therapy,” Tanyi said. “We’re seeing good efficacy signals, even at low doses, and limited toxicity.”

The results suggest that the therapy may be able to generate meaningful anti-tumor responses even in heavily pretreated populations.

Safety has been another major barrier for CAR T therapies, particularly in solid tumors. However, the KIR-CAR approach appears to mitigate some of these concerns.

No dose-limiting toxicities were observed in the initial cohorts. Cytokine release syndrome (CRS), a common side effect of CAR T therapy, occurred in 33% of patients but was limited to low-grade events. Notably, there were no cases of immune effector cell-associated neurotoxicity syndrome (ICANS), a more severe complication sometimes seen with CAR T therapies.

The ability to limit toxicity while maintaining activity is a key step toward broader application of cell therapies in solid tumors.

SynKIR-110 targets mesothelin, a protein expressed on the surface of several solid tumors but largely absent from normal tissues. This makes it an attractive target for immunotherapy, particularly in cancers such as ovarian cancer and mesothelioma, where treatment options are limited.

The trial results indicate that the therapy’s activity is not confined to a single tumor type, raising the possibility of broader applicability across mesothelin-expressing cancers.

The findings come amid growing efforts to adapt CAR T technology for solid tumors. While the approach has revolutionized hematologic malignancies, solid tumors present additional challenges, including immunosuppressive microenvironments, physical barriers to T cell infiltration, and antigen heterogeneity.

Researchers are exploring multiple strategies to address these barriers, including improved targeting, combination therapies, and next-generation receptor designs such as KIR-CAR.

As noted by CAR T pioneer Carl June, MD, advancing cellular therapies into solid tumors remains a central goal for the field.

The Phase I study continues to enroll patients, aiming for a 42‑person cohort to define the maximum tolerated dose ahead of Phase II. Early readouts show that CAR T expansion rises with dose, a pattern that may translate into stronger anti‑tumor activity at higher levels.

While still preliminary, the findings highlight the potential of multi‑chain CAR designs to sustain activity without added toxicity. If confirmed, KIR‑CAR therapies could usher in a new generation of engineered immune cells that more closely mirror natural immune regulation.

For now, the data offer a promising sign that CAR T innovation may finally be gaining ground in solid tumors.

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Experts usually describe the brain as a network of nerve cells (neurons) that send each other signals to pass along information. These neurons are maintained by another kind of brain cell, the star-shaped astrocyte, which ferries in nutrients and carries away waste.

The newly reported study, headed by Melissa Cooper, PhD, a postdoctoral fellow in the department of neuroscience at NYU Grossman School of Medicine, revealed that, like neurons, astrocytes form organized webs, which enable them to communicate with other specific astrocytes across the brain rather than only sending local, generalized signals. In some cases, the pathways were found to link areas that were not already joined together by neurons.

“For more than a century, neuroscientists have thought of neurons as the main actors in the brain,” said Cooper. “Yet our findings suggest that astrocytes, which are usually viewed as merely support cells, are also running their own widespread signaling pathway, adding another layer to how brain regions stay connected.” The team suggests that while their study was carried out in mice, not humans, the findings form the basis for future studies investigating how astrocyte networks might link with injury, disease, or aging and to learning and memory.”

Cooper is first and co-corresponding author of the team’s published work in Nature, titled “Astrocytes connect specific brain regions through plastic networks,” in which the researchers stated, “Astrocyte networks can directly link brain regions that are not connected by neurons, suggesting that previously unassociated brain regions communicate with one another through gap junction-coupled astrocytes.”

“Neuronal axons have traditionally been considered to be the primary mediators of functional connectivity among brain regions,” the authors wrote, and the role of communication mediated by astrocytes has been largely underappreciated. “This communication occurs through gap junctions—membrane channels that connect the cytoplasm of neighboring cells, enabling them to redistribute resources and share biochemical signals,” the team continued. “Studies using mice lacking astrocyte gap junctions have shown that these gap junctions are necessary for memory formation, synaptic plasticity, coordination of neuronal signaling, and closing the visual and motor critical periods.”

In earlier work, Cooper reported that in a mouse model of the visual neurodegenerative disease glaucoma, astrocytes can redistribute resources from astrocytes around healthy neurons to damaged neurons. Yet the team had no way to see whether this kind of support-cell network extended across the entire brain.

Cooper said the newly reported study is the first to map active, brain-wide communication networks built by astrocytes and to show that these pathways are highly specific. The research relied on a custom-built tracing tool that let the team follow the cells’ connections in far greater detail than had been possible using past methods. “Despite the importance of astrocyte gap junctional networks, studying them has been challenging,” the investigators noted. “Current methods such as slice electrophysiology disrupt network connectivity and introduce artefacts due to tissue damage.”

For their study, the researchers used a harmless virus to deliver “network tracers” into astrocytes in selected brain regions of lab mice. These tracers tagged small molecules as the molecules passed through the gap junctions linking one astrocyte to another, allowing the team to see which cells were part of the same signaling pathway.

The scientists then made the mice’s brains transparent and used a specialized microscope to capture three-dimensional images of every tagged astrocyte. By doing this across hundreds of mice, they could map astrocyte webs across brain areas. “These networks selectively connect specific regions, rather than diffusing indiscriminately, and vary in size and organization,” they reported. “We observe local networks that are confined to single brain regions and long-range networks that robustly interconnect multiple regions across hemispheres, often exhibiting patterns distinct from known neuronal networks.”

In another part of the study, the team assessed mice that were genetically engineered with astrocytes that lacked gap junctions. The communication networks largely disappeared, suggesting that the pathways are active and depend on these physical bridges.

“By challenging our understanding of how the brain communicates over long distances, our results may offer fresh insight into how it develops, ages, and behaves in conditions such as Alzheimer’s and Parkinson’s diseases,” said study co-senior author Shane A. Liddelow, PhD, an associate professor in the neuroscience and ophthalmology departments at NYU Grossman School of Medicine.

Another key finding was that astrocyte networks are dynamic. When the team trimmed whiskers on one side of the mice’s faces—“this manipulation is known to induce robust structural remodeling in neurons,” the team noted—a pathway from the region that processes whisker touch got smaller and reconnected to different astrocyte partners.

“The fact that astrocyte networks shrink and reroute after a loss of sensory signals suggests they may be shaped by experience,” said study co-senior author Moses V. Chao, PhD, a professor in the cell biology, neuroscience, and psychiatry departments at NYU Grossman School of Medicine. “It also raises the possibility that each of us has a somewhat unique pattern of connections molded by what our brains have learned and lived through.”

The authors plan to investigate which molecules move through the networks and to apply their tracing tool to models of brain disorders. They also hope to examine how these webs change during development and aging, said Chao.

Liddelow emphasized that while gap junctions and astrocytes exist in humans, it remains unknown whether the networks link the same regions in the same way as in mice. Nevertheless, in their paper, the team concluded that their findings “… establish foundation for future exploration of how astrocyte network structure and function are shaped by injury, disease, development, aging and experience-dependent processes such as learning and memory.”

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Normal function of the peripheral vasculature requires communication and cooperation between the vascular endothelium and macrophages. “Monocytes patrol the vascular endothelium and remove damaged cells, and intimal-resident macrophages maintain a nonthrombogenic endothelial state,” wrote the authors of a study led by Zhen Chen, PhD, at City of Hope. They explained that under stress, macrophages can modulate vascular remodeling and in certain conditions, like cancer, they “can secrete inflammatory mediators to disrupt endothelial cell tight junctions and increase endothelial cell permeability.”

The team decided to explore the cellular cross-talk between macrophages and endothelial cells, as well as the resulting vascular function, to better understand the mechanisms behind peripheral artery disease induced by diabetes.

They published their work in a paper titled “Diabetes-induced TREM2–endothelial cell signaling impairs ischemic vascular repair” in Science Translational Medicine.

Using samples collected post-mortem from either donors with type 2 diabetes or donors without diabetes, the researchers aimed to systematically map the interactions between macrophages and endothelial cells in the arterial wall. They “leveraged single-cell RNA sequencing and spatial transcriptomics to profile human mesenteric arteries…generating a transcriptome and interactome atlas of diabetic vasculature.”

Their analysis identified increased expression in paired genes between macrophages and endothelial cells. Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene previously identified as connected with metabolic disease, atherosclerosis, cancer, and neurodegeneration. In macrophages, TREM2 had increased expression in tissues from donors with type 2 diabetes, with concurrent expression of the TREM2 ligands in endothelial cells. Macrophages with increased TREM2 presented with a foamy cell structure, indicative of a pro-inflammation phenotype. Additionally, these cells had a proinflammatory gene profile.

Inhibiting TREM2 in vitro resulted in proinflammatory responses in macrophages and endothelial cells, along with increased migration of endothelial cells. To replicate TREM2 inhibition in vivo, the researchers used a mouse model for diabetes with hindlimb ischemia and treated them with a neutralizing antibody. This resulted in symptom improvement and improved blood vessel flow. Alternatively, activation of TREM2 with an agonist resulted in reduced blood flow and vascular damage.

Further analysis of human donor samples “confirmed elevated endothelial cell TREM2 signaling in human peripheral arterial disease, particularly in the setting of diabetes mellitus, highlighting its translational relevance.”

Together, these data show how TREM2 is involved with macrophage-endothelial cell communication within the peripheral vasculature. The authors pointed out that while TREM2 is a therapeutic target in treating Alzheimer’s disease and cancer, it might also have utility in treating peripheral artery disease.

“Plasma sTREM2 may be useful as a circulating marker of endothelial/vascular dysfunction in peripheral artery disease for risk stratification and outcome prediction,” they wrote. “In addition, our findings suggest caution when considering TREM2-enhancing therapeutics, particularly in individuals with existing diabetes mellitus and ischemic disease.”

This work underscores the need for more research into the details of disease mechanistic function to both better understand the cause of disease and to identify potential therapeutic targets.

“Future studies will need to dive deeper into how insulin deficiency or resistance and hyperglycemia activate macrophages to augment TREM2 expression and induce vascular dysfunction,” wrote Michael Chang, Michael T. Patterson, PhD, and Jesse Williams, PhD, in a related focus.

“Overall, the work of Malhi et al. advances our mechanistic understanding of type 2 diabetes-driven peripheral artery disease and has laid the foundation for developing targeted therapies for a disease with few viable treatment options,” they concluded.

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The partnership leverages both companies’ GMP manufacturing facilities, technical expertise, and regional networks to fast-track the development, manufacturing, and global expansion of client programs, according to officials at both organizations.

This partnership is designed to enable a streamlined “dual hemisphere” workflow. By providing a direct route between U.S. and APAC manufacturing hubs, the collaboration could help remove a number of the regulatory and logistical complexities of international expansion.

Most importantly, facilitating in-country manufacturing for in-country clinical trials ensures regional supply chains can meet the specific needs of local patient populations, greatly reducing lead times and accelerating the path to commercialization, pointed out Wade Macedone, CEO at Andelyn.

“Our partnership with ENCell is a powerful step forward in Andelyn’s mission to help bring life-saving therapies to patients worldwide,” he said. By joining forces with such a respected leader in South Korea, we are not just expanding our global footprint; we are leveraging our unique strengths to deliver a truly seamless international manufacturing network.”

“This partnership with Andelyn represents a significant step in expanding the global CGT ecosystem,” added Jong Wook Chang, PhD, CEO of ENCell. “By combining Andelyn’s expertise in viral vector development and cGMP manufacturing with ENCell’s clinical and manufacturing capabilities across APAC, we are establishing a seamless manufacturing platform connecting the United States and Asia-Pacific.

“Together, we will enable more efficient development and scalable production of gene therapies, supporting our clients from early-stage development through global clinical trials and commercialization.”

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