Single‑cell RNA sequencing has reshaped immunology by revealing which genes are switched on across thousands of cells at once. But RNA alone can be misleading, especially for cytokines. However, RNA is only a set of instructions; proteins carry out the action. And for cytokines, RNA levels often fail to predict how much protein a cell actually produces. “In immune cells, RNA and protein don’t always rise and fall together,” said co‑senior author Emiliano Cocco, PhD, an assistant professor of biochemistry and molecular biology at the Miller School.

CIPHER‑seq (Cytokine Intracellular Protein High-throughput Expression with RNA-sequencing) was designed to close that gap. Developed by researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, together with collaborators at UCSF and the Helen Diller Family Comprehensive Cancer Center, the method gently preserves cells and captures multiple molecular layers at once. From a single immune cell, CIPHER‑seq can quantify genome‑wide RNA, surface proteins, intracellular proteins, and cytokines that have not yet been released—creating a more complete snapshot of immune activity than RNA‑only approaches.

“RNA gives us clues about where a cell is headed,” said co‑senior author Justin Taylor, MD, a Sylvester physician-scientist. “Proteins show us where it actually arrives, and this clearer picture could help scientists design better immunotherapies and help clinicians predict which patients are most likely to benefit from them.”

The team validated the platform by stimulating peripheral blood mononuclear cells (PMBCs) and tracking their responses. According to the study, CIPHER‑seq captured robust induction of key cytokines—including interferon‑gamma and tumor necrosis factor—while also resolving metabolic remodeling during activation. Importantly, the method revealed the timing of these events: RNA signals rose first, followed by delayed but consistent protein accumulation. First author Avni Bhalgat, PhD, described it as “seeing the plan before the action. Cytokines help determine whether immune cells attack cancer, ignore it, or even help tumors grow.”

The researchers also compared CIPHER‑seq with standard single‑cell workflows and found a notable difference: cells processed with CIPHER‑seq showed far fewer mitochondrial stress signatures. Some existing protocols inadvertently damage cells during preparation, triggering artificial stress responses. By reducing these artifacts, CIPHER‑seq provides a cleaner readout of immune behavior.

The authors emphasize that this multimodal view is especially valuable for studying cancer, inflammation, and treatment resistance—contexts where cytokine timing and protein abundance can shape therapeutic outcomes. “The platform helps us move beyond inference and toward understanding how immune responses truly unfold—one cell at a time,” Taylor added. By tracking RNA and protein together, CIPHER‑seq moves researchers beyond inference and toward a step‑by‑step understanding of how immune responses unfold.

The post New Single‑Cell Platform Tracks RNA and Protein in Immune Signaling appeared first on GEN - Genetic Engineering and Biotechnology News.

“This transaction will advance Neurocrine’s mission to deliver life-changing treatments while accelerating our revenue growth and portfolio diversification strategy,” Kyle W. Gano, PhD, Neurocrine’s CEO, said in a statement.

The acquisition would bolster Neurocrine’s offerings to include three treatments that have already reached the market:

• Crenessity^® (crinecerfont), a treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency that received FDA approval in December 2024
• Ingrezza^® (valbenazine), a vesicular monoamine transmitter 2 (VMAT2) drug approved in 2017 as a treatment for tardive dyskinesia and the chorea associated with Huntington’s disease
• Vykat XR (diazoxide choline), approved last year as the first and only therapy indicated to treat hyperphagia in patients ages four and older with Prader-Willi syndrome (PWS).

“Neurocrine is the right strategic partner to expand the reach of Vykat XR in the Prader-Willi syndrome community given their experience in endocrinology and rare disease and their proven ability to execute successful commercial launches,” stated Anish Bhatnagar, MD, Soleno’s chairman and CEO. “We are excited to accelerate Vykat XR’s impact for PWS patients following completion of the transaction by leveraging Neurocrine’s strong commercial capabilities.”

Soleno finished 2025 with $190.4 million in net revenue from sales of Vykat XR—including $91.7 million generated during the fourth quarter, pushing the company to profitability with positive net income of $20.9 million.

‘A little surprising’

Stifel analysts Paul Matteis and James Condulis called the planned acquisition “a little surprising” since Vykat XR is projected to garner approximately $400 million in annual net revenue, he commented in a note reported by Bloomberg News.

Vykat XR won FDA approval in March 2025. From then through December 31, 859 active patients were prescribed the drug by 630 unique prescribers (136 of them in Q4), while the company received 1,250 patient start forms (207 in Q4).

Neurocrine expects Vykat XR’s numbers to improve in coming years, since the drug is positioned as a foundational first-line therapy for PWS and is supported by a patent portfolio that is expected to protect the drug’s exclusivity into the mid-2040s.

Vykat XR would join Neurocrine’s marketed portfolio which includes Ingrezza and Crenessity. Ingrazza racked up blockbuster net revenue numbers of $2.51 billion up 9% year-over-year (including $657.5 million during Q4, up 7% from the year-ago quarter). Neurocrine has credited double-digit prescription volume growth in total prescriptions and new (first-time) prescriptions, partially offset by a lower net price that the company called new “formulary access investments” designed to support long-term growth.

Crenessity generated $301.2 million in net product sales last year for Neurocrine, including $135.3 million in the fourth quarter, reflecting 2,048 total new patient enrollment start forms, 431 of them in Q4 2025.

Neurocrine reasons that the three drugs will deliver sustained revenue growth for the combined company through the end of the decade.

Also for Neurocrine, a buyout of Soleno presents a “more sensible way into metabolic disease” than by developing its own pipeline candidates, which are in preclinical phases, and risking competitive and regulatory challenges, BMO Capital Markets analyst Evan Seigerman observed in a research note reported by Reuters.

Neurocrine has disclosed plans to begin Phase I studies this year for two preclinical obesity candidates: NBIP-‘2118, a CRF2 agonist; and ‘NBIP-‘1968, a combination of ‘2118 and the company’s own GIP (glucose-dependent insulinotropic polypeptide)/ GLP-1 (glucagon-like peptide-1) preferring triple agonist, which Neurocrine calls “light” on glucagon activity.

News of a potential buyout of Soleno by Neurocrine was first reported Sunday by the Financial Times.

Soleno investors signaled approval of the buyout Monday by sending shares to $52.25, up 32% from Thursday’s close of $39.49 (Markets were closed Friday for Good Friday). However, Neurocrine’s investors weren’t as supportive of the deal as that company’s shares barely budged, closing at $132.48, up 0.67% from $131.60 on Thursday.

Second thoughts?

A potential reason: Neurocrine investors may have second thoughts about a deal that would add to its pipeline Vykat XR, whose prescribing label includes warnings and precautions about past reports of hyperglycemia and fluid retention/edema, as Sumant Kulkarni, a senior analyst covering biotechnology with Canaccord Genuity, commented in a research note.

“We believe NBIX would have to articulate its plans very well for investors to display enthusiasm from the get-go,” Kulkarni wrote.

Yet two things could work in Neurocrine’s favor, Kulkarni added: The company’s solid track record of commercialization as seen with Ingrezza and Crenessity, and the prospect of adding to the portfolio Vykat XR given its approval for a rare form of obesity.

San Diego-based Neurocrine reported approximately 2,000 employees as of December 31, 2025, with plans during the first quarter to complete the expansion of sales teams for Ingrezza and Crenessity “to maximize our commercial momentum.” Soleno is based in Redwood City, CA, and reported a workforce of 182 full-time employees as of the end of 2025.

At $53 per share cash, the purchase price represents a premium of about 34% above Soleno’s closing share price Thursday, and a premium of 51% to Soleno’s 30-day volume-weighted average price (VWAP).

The boards of both Neurocrine and Soleno have approved the transaction, which is expected to close within 90 days subject to satisfying customary closing conditions that include receipt of regulatory approvals.

Neurocrine will acquire Soleno by launching a tender offer for that company’s outstanding shares. Following a successful completion of the tender offer, a wholly owned subsidiary of Neurocrine will merge with Soleno, and the outstanding Soleno shares not tendered in the offer will be converted into the right to receive the same $53 per share in cash paid in the tender offer.

Consummation of the tender offer is subject to the tender of at least a majority of the outstanding shares of Soleno, the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, and other customary conditions.

Neurocine said it will fund its acquisition of Soleno using a “modest amount” of pre-payable debt plus cash on hand. Neurocrine reported $1.48 billion in cash, cash equivalents, and marketable securities as of December 31, 2025—up 37.5% from $1.076 billion a year earlier.

The post Neurocrine Grows in Endocrinology, Rare Disease with $2.9B Soleno Buyout appeared first on GEN - Genetic Engineering and Biotechnology News.

Covalent small-molecule drugs have shown great success in cancer therapy by forming irreversible bonds with their targets. This has inspired efforts to extend covalent strategies to protein therapeutics, especially engineered miniproteins. However, their development is limited by a kinetic mismatch. Miniproteins are rapidly cleared in vivo, while covalent bond formation is typically slow. In addition, high-throughput platforms for systematically optimizing covalent protein reactivity have been lacking.

To address this challenge, the researchers proposed that precise spatial positioning of chemical warheads within protein scaffolds could enable molecular preorganization, thereby accelerating covalent bond formation without increasing intrinsic reactivity (see figure).

Based on this concept, the team created a high-throughput platform that combines yeast surface display with chemoselective protein modification to screen diverse crosslinkers and millions of protein variants. The platform enables rapid and irreversible target engagement.

Using this platform, the researchers developed a covalent antagonist targeting PD-L1, termed IB101. Structural analysis revealed that IB101 forms a defined binding pocket that precisely positions the active moiety in a reactive conformation, greatly accelerating covalent bond formation.

Functionally, IB101 effectively blocks the PD-1/PD-L1 immune checkpoint pathway and demonstrates strong antitumor activity in mouse models. Notably, despite its short in vivo half-life, IB101 achieves durable target engagement and tumor suppression, outperforming conventional antibody-based therapies under comparable conditions, according to the scientists.

The platform was further applied to cytokine engineering, leading to the development of a covalent IL-18 variant, IB201. This engineered cytokine rapidly forms a covalent interaction with its receptor, enhancing signaling strength and duration. In vivo studies showed that IB201 induces potent antitumor immune responses without detectable systemic toxicity. These results highlight the potential of covalent engineering to improve the efficacy and safety of cytokine-based therapies.

Beyond immunotherapy targets, the platform was also applied to develop a covalent inhibitor targeting the receptor-binding domain (RBD) of SARS-CoV-2. This molecule showed durable viral neutralization, demonstrating the versatility of the approach across different therapeutic modalities, note the researchers, adding that the study establishes a general strategy for engineering fast-acting covalent protein therapeutics.

By enabling covalent bond formation on timescales compatible with rapid in vivo clearance, the platform overcomes a fundamental limitation in the field, say the scientists. These findings, they continue, provide a new framework for designing biologics with both rapid kinetics and sustained target engagement, with broad implications for cancer immunotherapy, antiviral therapy, and beyond.

The post High-Throughput Platform for Fast-Acting Covalent Protein Therapies appeared first on GEN - Genetic Engineering and Biotechnology News.

Headquartered in Munich, privately held Tubulis has developed next-generation ADC candidates based on its own conjugation, linker and payload technologies intended to more selectively deliver diverse payloads to tumors deemed to be of high unmet need. The companies said Tubulis’ programs and platforms have broad potential across multiple tumor types, complementing Gilead’s development and commercialization expertise in oncology.

“We like the strategic fit and deal terms of the Tubulis (private) acquisition,” Daina M. Graybosch, PhD, senior managing director, immuno-oncology and a senior research analyst at Leerink Partners, wrote this morning in a research note. “This is more than an oncology bolt-on; we see real platform value in application of Tubulis’ ADC technologies to other therapeutic areas, namely virology.”

Tubulis’ lead pipeline candidate, TUB-040, is a sodium-dependent phosphate transport protein 2B (NaPi2b)-targeting topoisomerase-I inhibitor (TOPO1i) ADC that is now under study in the Phase Ib/II NAPISTAR1-01 trial (NCT06303505) assessing its safety, pharmacokinetics, and preliminary efficacy as a treatment for platinum-resistant ovarian cancer and non-small cell lung cancer (NSCLC).

In October at the European Society for Medical Oncology (ESMO), Graybosch noted, Tubulis presented data for TUB-040 showing a confirmed 50% overall response rate (ORR) and a 60% unconfirmed ORR across dose levels and irrespective of target antigen—results that were competitive with more mature datasets from leading TOPO1i ADCs.

“Though the dataset was early, and our primary outgoing question was how durability would mature, we suspect that Gilead saw durability maturing positively in their diligence,” Graybosch added. “If TUB-040 proves active in NSCLC, the program could complement their Trodelvy and IO [immune-oncology] lung programs. We wonder if Gilead saw early clinical NSCLC data in their diligence and if excitement around the emerging signal drove some of Tubulis’ valuation.”

Another Tubulis pipeline candidate, TUB-030, is a 5T4-targeting ADC that according to the companies has shown promising initial clinical data across various solid tumor types. TUB-030 is currently under study in the Phase I/IIa 5-STAR 1-01 trial (NCT06657222), a first-in-human study which aims to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TUB-030 as a monotherapy in patients with advanced solid tumors. Tubulis has said it is developing TUB-030 for up to 13 undisclosed solid tumor indications.

Partners since 2024

The acquisition deal follows a two-year, up-to-$465 million collaboration with Tubulis launched in December 2024. Gilead gained access to Tubulis’ Tubutecan and Alco5 platforms after signing an exclusive option and license agreement to discover and develop an ADC against a solid tumor target.

At the time, Gilead agreed to pay Tubulis $20 million upfront, received an option that if exercised would have given Tubulis an additional $30 million—plus up to $415 million in payments tied to achieving development and commercialization milestones, as well as mid-single to low double-digit tiered royalties on sales of marketed products resulting from the collaboration.

“Today’s agreement follows a two-year collaboration with Tubulis, which has given us strong conviction in their programs and research capabilities,” Gilead Chairman and CEO Daniel O’Day said in a statement. “The agreement to acquire Tubulis is a significant milestone in Gilead’s progress in oncology. The company brings a clinical-stage candidate that is a potential new treatment for ovarian cancer, as well as a next-generation ADC platform and a promising early pipeline.”

“Bringing this potential into Gilead would further expand what is already the strongest and most diverse pipeline in our company’s history,” O’Day declared.

Investors appeared less enthusiastic about the acquisition, as shares of Gilead dipped 1.7% in early Tuesday trading to $137.80 as of 12:01 p.m. ET.

Tubulis is Gilead’s third announced acquisition this year. The biotech giant announced plans in March to buy Ouro Medicines for up to $2.18 billion, and in February agreed to acquire Arcellx for up to $7.8 billion—for which it agreed last week to extend its tender offer until 5 p.m. ET on April 24.

Under the acquisition deal, Gilead agreed to acquire all of the outstanding equity of Tubulis for $3.15 billion in upfront cash payable at closing, and up to $1.85 billion in payments tied to milestones.

The transaction is expected to close in the second quarter subject to expiration or termination of specified regulatory filings and other customary conditions.

Upon closing of the deal, Tubulis will operate as a dedicated ADC research organization within Gilead, with the Munich site serving as a hub for ADC innovation, building on its integrated discovery, manufacturing, and clinical capabilities to advance next generation ADCs.

Gilead said it plans to finance the transaction with a combination of cash on hand and senior unsecured notes. Gilead finished 2025 with $10.605 billion of cash, cash equivalents and marketable debt securities, up from $9.991 billion as of December 31, 2024.

The post Gilead to Acquire Tubulis for Up to $5B, Expanding Cancer ADC Capabilities appeared first on GEN - Genetic Engineering and Biotechnology News.

“A key component of our approach is to begin by understanding the biological mechanisms at play,” said Sergio Catz, PhD, professor at Scripps Research and corresponding author of the study. “By accomplishing this first, we can more easily target the pathway driving inflammation without affecting other important processes.” 

Current autoimmune disease treatments, such as hydroxychloroquine, function by broadly blocking endosomes. While effective, this approach can lead to significant side effects, including gastrointestinal problems and, less commonly, vision damage, that cause patients to stop treatment. 

The authors focused on two proteins, Munc13-4 and syntaxin 7, that bind together to activate Toll-like receptors (TLRs), immune sensors that activate endosomes. This mechanism plays a key role in detecting foreign DNA and RNA from viruses and bacteria. In autoimmune diseases, TLRs become overactive and trigger chronic, damaging inflammation in the absence of a threat. 

The team screened roughly 32,000 compounds and identified molecules that specifically block the Munc13-4–syntaxin 7 interaction without disrupting other cellular functions. Given that Munc13-4 is found mainly in immune cells, the compounds offer a targeted approach to reduce inflammation. 

“Most treatments for autoimmune diseases manage symptoms; they don’t change the underlying course of the disease,” said Hugh Rosen, MD, PhD, professor at Scripps Research and co-author of the study. “What’s exciting about this approach is its potential to be disease-modifying: targeting the specific molecular machinery that drives inflammation, rather than broadly suppressing the immune system.” 

Notably, the study screened compounds in an intact cellular environment which contrasts from many drug screening approaches, which extract proteins from the cell. 

“By maintaining the proteins in their natural environment, we increase the likelihood that compounds we find will actually work in living cells,” said Jennifer Johnson, PhD, first author and senior staff scientist at Scripps Research. 

The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers, including immune system activators IL-6 and IFN-γ, and the enzyme myeloperoxidase, dropped significantly in animals that were treated. 

ENDO12 treated animals demonstrated normal antiviral immune response when exposed to a virus. This selectivity addresses the concern that dampening inflammation with immunosuppressive drugs may leave patients vulnerable to infections. 

Looking ahead, the team will test ENDOtollins in models that more closely mimic human autoimmune diseases and evaluate the compounds’ chemistry for potential clinical use. 

Beyond autoimmune conditions, the researchers suggest ENDOtollins might help treat cytokine storms, the dangerous immune overreactions seen in patients with severe COVID-19 and as a side effect of CAR T cancer therapy. Both involve excessive IL-6 and runaway inflammation. 

While translating these findings into treatments for patients remains a long-term goal, Catz emphasizes that the mechanistic insights are valuable in their own right. ENDOtollins can serve as precision tools to probe other cellular processes regulated by endosomes and lysosomes, including pathways implicated in neurodegeneration and immune dysfunction.  

The post Autoimmune Disease-Related Inflammation Reduced with ENDOtollins Drug appeared first on GEN - Genetic Engineering and Biotechnology News.

Researchers from the Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Sun Yat-sen University, Guilin Medical University, and collaborating institutions reported the findings in Environmental Science and Ecotechnology. Their study, “Microplastics accumulate in human bile and drive cholangiocyte senescence,” provides the first direct evidence that microplastics are not only present in bile but may also contribute to mitochondrial dysfunction and premature aging in cholangiocytes, the epithelial cells that line the bile ducts.

The team collected bile from 14 surgical patients (five without gallstones and nine with gallstones) and used a multimodal analytical approach—pyrolysis–gas chromatography–mass spectrometry, laser direct infrared spectroscopy, and scanning electron microscopy—to characterize the particles. According to the paper, “we show the universal presence of microplastics in human bile,” identifying six polymer types dominated by polyethylene terephthalate and polyethylene, with most particles measuring 20–50 μm. Patients with gallstones carried substantially higher microplastic burdens, raising questions about whether biliary stasis or altered bile composition may influence microplastic retention.

One of the most intriguing findings is that melatonin, a widely used antioxidant, partially reversed the mitochondrial and inflammatory damage. While far from a therapeutic recommendation, the result hints at a potential intervention point and gives the study translational relevance.

The work reframes the biliary system as something far more active than a simple transit channel. The data indicate that bile can serve as a reservoir for microplastics and that prolonged exposure may age cholangiocytes by driving mitochondrial dysfunction. The partial rescue with melatonin adds a mechanistic foothold for future intervention, even as the authors caution that broader human studies are essential.

For biotech, the implications are broad. The work highlights bile as a clinically accessible matrix for exposure assessment, opening the door to new diagnostics for environmental toxicology. The mitochondrial stress signature aligns with pathways already being targeted by companies developing senolytics, mitoprotective agents, and anti‑inflammatory therapeutics. The authors wrote that the research provides “a mechanistic foundation for assessing the health risks of plastic pollution and developing therapeutic interventions for environmentally driven biliary disorders.”

The post Microplastics in Human Bile Drive Mitochondrial Dysfunction and Senescence appeared first on GEN - Genetic Engineering and Biotechnology News.

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Panelists:

Rodolphe Barrangou, PhD

North Carolina State University

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Panelist

Rodolphe Barrangou, PhD

Rodolphe Barrangou, PhD, is the T. R. Klaenhammer Distinguished Professor at North Carolina State University, where he leads the CRISPR Lab. Rodolphe spent nine years at Danisco and DuPont, where he made seminal contributions in the functional characterization of CRISPR as a microbial immune system. He has been at NC State since 2013.

For his CRISPR work, Rodolphe has received several international awards, notably the Canada Gairdner International Award, and has been elected to the National Academy of Sciences, the National Academy of Engineering, and the National Academy of Inventors. Rodolphe is a scientific co-founder of Intellia Therapeutics, Locus Biosciences, TreeCo, Ancilia Biosciences, and CRISPR Biotechnologies, and an advisor to Inari and the IGI. He is also the founding Editor in Chief of The CRISPR Journal (published by Mary Ann Liebert, Inc., a Sage partner), which launched in 2018.

Rodolphe holds a degree from Paris Descartes University and a PhD in functional genomics from NC State.

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It has been almost 25 years since the acronym “CRISPR” was first coined. Since then, CRISPR has become a household word, a star of books and films, and a Nobel Prize–winning discovery. This powerful and disruptive genome editing technology has transformed countless fields, including gene therapy, xenotransplantation, de-extinction and agbiotech. Researchers continue to build on the CRISPR chassis, devising new platforms for bespoke genome editing. But major questions remain around clinical safety, commercial development, ethical deployment, and regulatory oversight.

In the first of a new series of GEN Keynote Webinars, Professor Rodolphe Barrangou, PhD (North Carolina State; EIC, The CRISPR Journal) offers a front-row perspective of the CRISPR revolution, the seminal advances, clinical highlights, and rising applications. Almost two decades ago, Barrangou provided the first experimental demonstration of the functional role of CRISPR. With numerous advisory and entrepreneurial activities in the gene editing space, Barrangou is the ideal guide to discuss CRISPR’s progress in the clinic; the state of the CRISPR toolbox; and the regulatory roadblocks and ethical challenges that will shape the application of CRISPR in agbiotech, germline editing, and other arenas.

Registration for this GEN Keynote Webinar is free. Following this live presentation, Dr. Barrangou will answer audience questions.

Produced with support from:

The post CRISPR at 25: The Past, Present, and Future of Genome Editing appeared first on GEN - Genetic Engineering and Biotechnology News.

Dendritic cells alert and activate tumor-killing immune cells as a critical part of anticancer immune response. The authors found that tumors reduce dendritic cell function by minimizing mitochondrial fitness to prevent anticancer immune response. Correspondingly, boosting mitochondrial function in dendritic cells enhances antitumor immune activity and strengthens the efficacy of existing immunotherapies.  

Within the nutrient-sparse tumor microenvironment, dendritic cells progressively lose mitochondrial activity, which drives cell dysfunction and weakens immune defenses against cancer. When dendritic cells with high mitochondrial activity were introduced into tumors in preclinical mouse models, results showed that immunogenic activity was restored while improving tumor control.  

“We found that tumors reprogram mitochondrial metabolism in dendritic cells, reducing their ability to activate the immune system against cancer,” said Hongbo Chi, PhD, St. Jude Department of Immunology chair and corresponding author of the study. “By enhancing mitochondrial function, we could restore dendritic cell activity and rescue antitumor immunity.”  

Immunotherapies for cancer, such as immune checkpoint blockade, have greatly improved care for many malignancies, but have not been successful in all cancers. To determine whether these findings could improve immunotherapy effectiveness in tumor-bearing mice, the authors evaluated the administered dendritic cells with high mitochondrial activity in combination with immune checkpoint blockade. 

“We saw the most pronounced therapeutic effect in mice treated with the combination of dendritic cells that had high mitochondrial activity and immune checkpoint blockade,” said co-first author Zhiyuan You, PhD, researcher at St. Jude Department of Immunology. “Those combinations synergistically slowed or stopped tumor growth and extended survival far more than either treatment alone.”  

To test long-term effects, the researchers exposed combination therapy treated mice to a new tumor after a few months. New tumor growth stopped for these mice, indicating durable, long-term immune memory. 

To better understand the relationship between mitochondrial function and dendritic cells, the researchers examined metabolic pathways affected by the tumor microenvironment. They identified a signaling axis composed of two proteins, OPA1 and NRF1, that regulate communication between mitochondria and the nucleus. Expression was greatly downregulated in dendritic cells during tumor progression and acted as a metabolic switch to shut down dendritic cell immunogenic activity.  

“We’re seeing a direct regulation of dendritic cells by the tumor microenvironment,” said co-first author Jiyeon Kim, PhD, researcher at St. Jude Department of Immunology. “We have characterized how that results in mitochondrial reprogramming of dendritic cells to benefit cancer, giving us new opportunities to reverse the process.”  

The study’s mechanistic insights enable new directions to rewire dendritic cell function and enhance cancer treatments.  

“These findings reinforce the central role of dendritic cells in cancer immunity,” Chi said. “By exploring their mitochondrial function in the tumor microenvironment, we have provided a proof-of-principle of how we may be able to improve the next generation of immunotherapies.” 

The post Immunotherapy Enhanced by Restoring Mitochondrial Function in Dendritic Cells appeared first on GEN - Genetic Engineering and Biotechnology News.

The new method, called MethylScan, works by analyzing cell-free DNA (cfDNA), tiny fragments of genetic material released into the blood when cells die. Because cells from every organ shed DNA into the bloodstream, cfDNA carries molecular signals that reflect what is happening throughout the body.

The researchers say MethylScan could represent a powerful and more affordable approach to early disease detection and comprehensive health monitoring. “Early detection is crucial,” said research lead Jasmine Zhou, PhD, a professor of pathology and laboratory medicine and investigator at the UCLA Health Jonsson Comprehensive Cancer Center. “Survival rates are far higher when cancers are caught before they spread. If you detect cancer at stage one, outcomes are dramatically better than at stage four.” Zhou is senior author of the team’s published paper in PNAS, titled “Toward the simultaneous detection of multiple diseases with a highly cost-effective cell-free DNA methylome test.”

“When cells die, they do not simply vanish; they leave behind molecular traces, including cell-free DNA (cfDNA) in the blood stream,” the authors wrote. “cfDNA is a mixture of DNA fragments released from various organs, offering valuable insights into the health of these organs.” Zhou added, “Every day, 50 to 70 billion cells in our body die. They don’t just disappear, their DNA goes into the bloodstream. That means we already have information from all our organs circulating in the blood.”

The idea of using blood to detect cancer, sometimes called a liquid biopsy, isn’t new. Some tests already look for mutations in tumor DNA to screen for certain cancers. But those tests often focus on a limited number of genetic changes and can be expensive, in part because they require deep sequencing to detect faint tumor signals.

Instead of searching for mutations, the UCLA team examined DNA methylation, chemical tags attached to DNA that help regulate gene activity. Methylation patterns differ by tissue type and can change when cells become cancerous or diseased. “Unlike an individual’s genome, which remains largely stable across tissues and over time (except for rare somatic mutations), the DNA methylome is tissue-specific and dynamically changes with the tissue’s disease status,” the team continued.

“DNA methylation reflects the health status of a tissue,” said co-corresponding author Wenyuan Li, PhD, a professor of pathology and laboratory medicine at UCLA and co-corresponding author of the study. “It’s a very informative signal.”

The challenge is that most cell-free DNA in the bloodstream doesn’t come from tumors or injured organs. About 80% to 90% originates from normal blood cells. That creates background noise, making it difficult and costly to detect the relatively rare fragments that might signal early cancer. “A major challenge in using the cfDNA methylome for disease detection is the high cost of sequencing,” the team stated. “In healthy individuals, about 85% of cfDNA originates from blood cells, creating substantial background noise that can obscure cfDNA from tumors or diseased organs.” And as the authors further pointed out, “Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci.”

For their newly reported research the team built on past work to develop a technique to remove much of the background DNA before sequencing. Using specialized enzymes, they selectively cut away unmethylated DNA fragments that largely come from blood cells. By designing a genome-wide hybridization panel, the captured DNA fragments are enriched for methylated DNA from solid organs, including those that are potentially diseased. “The MethylScan method is a targeted methylation assay that combines Methylation-Sensitive Restriction Enzymes (MSRE) digestion with a custom panel to enrich hypermethylated cfDNA from tissues beyond blood, enabling cost-effective detection of multiple diseases,” they wrote.

By removing the noise, the researchers say they can dramatically reduce the amount of sequencing needed, lowering costs while maintaining sensitivity. Achieving an effective sequencing depth of 300× per sample requires only 5 Gb of data, which would cost less than $20 if the price per gigabase is under $4.

To test the accuracy of MethylScan, the researchers analyzed blood samples from 1,061 people, including patients with liver, lung, ovarian and stomach cancers; individuals with liver diseases such as hepatitis B, hepatitis C, alcohol-related liver disease, and metabolic-associated liver disease; people with benign lung nodules; and healthy participants. Machine learning algorithms were then applied to analyze the complex methylation data.

For multi-cancer detection, the test achieved a high level of overall accuracy. At a specificity of 98%, meaning few false positives, it detected about 63% of cancers across all stages and roughly 55% of early-stage cancers. The test also performed well in liver cancer surveillance among high-risk individuals, including those with liver cirrhosis or HBV, detecting nearly 80% of cases at a specificity of just over 90%, meaning a less than 10% false positive rate.

Beyond simply detecting cancer, the methylation patterns helped identify where in the body a signal was coming from, known as the tissue of origin. “Being able to trace signals back to their source is important because a positive blood test needs to be followed by imaging or other diagnostic procedures directed at the right organ,” said Li.

MethylScan can work like a health radar for the body. By reading DNA signals in the blood, it can tell when specific organs, such as the liver or lungs, are under stress or damaged, even without knowing the disease in advance. The researchers also showed that the blood test could distinguish between different types of liver disease, including viral hepatitis and metabolic-associated liver disease. It correctly classified about 85% of patients, suggesting blood-based DNA testing could reduce the need for invasive liver biopsies.

Although larger prospective trials will be needed to confirm its performance in real-world screening, Zhou said the work represents an important step toward a single, affordable blood assay that can detect a broad spectrum of diseases earlier and more comprehensively than current methods allow.

“Because cfDNA in blood originates from multiple organs, and ‍MethylScan captures a broad spectrum of robust hypermethylation markers, this assay has the potential to detect a variety of diseases, provided that appropriate training cohorts are available,” the investigators stated. “This versatile approach enables affordable, wide-ranging cfDNA tests that can identify various health conditions simultaneously, with the potential to transform early disease detection and health monitoring across diverse clinical settings.

Zhou added, “This study demonstrates that blood-based methylation profiling can deliver clinically meaningful information across multiple diseases. It’s an exciting advancement that brings us closer to realizing the dream of a single assay for universal disease detection.”

The post Low-Cost, Single Sample Blood Test Detects Different Cancers, Liver Disorders, and Other Diseases appeared first on GEN - Genetic Engineering and Biotechnology News.

The collaboration brings together OneCyte’s proprietary single-cell platform for high-throughput and high-speed clone selection with Kemp Proteins’ molecular engineering capabilities, including its machine learning–driven platform, PROTiQ.

Biopharma companies continue to face significant challenges in cell line development, including long development cycles, suboptimal yields, and high failure rates, particularly for novel and complex molecules, according to Konstantinos Tsioris, PhD, co-founder and president of OneCyte. These challenges can delay regulatory timelines and slow the progression of therapies into the clinic.

The OneCyte-Kemp partnership addresses these pain points by integrating predictive in silico design with rapid and high throughput experimental validation, say officials at both companies. As part of the workflow, amino acid sequences are evaluated using Kemp’s PROTiQ platform to assess developability risks, identify sequence liabilities, and generate structural insights.

The optimized candidates are then paired with OneCyte’s high-performance cell line development platform, which reportedly enables identification of elite clones with higher productivity.

Unlike traditional, rigid development workflows, this integrated approach is designed to adapt quickly to the evolving needs of new therapeutic modalities, notes Tsioris.

“By combining our single-cell technology with Kemp’s deep expertise in protein expression, we are confident that we can address the hardest challenges associated with new modalities, delivering faster timelines and industry-leading titers,” he continues.

“OneCyte’s class-leading single-cell technology, stacked on top of our molecular design and expression capabilities, will provide a powerful and differentiated solution for our global biopharma customers,” says Michael Keefe, CEO of Kemp Proteins.

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